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Chapter 9: Adrenoceptor Agonists & Sympathomimetic Drugs

Katzung's Basic and Clinical Pharmacology, 16th Edition Italo Biaggioni, MD & Vsevolod V. Gurevich, PhD

CASE STUDY

A 68-year-old man presents with a complaint of lightheadedness on standing that is worse after meals and in hot environments. Symptoms started about 4 years ago and have slowly progressed to the point that he is disabled. He has fainted several times but always recovers consciousness almost as soon as he falls. Other symptoms include slight worsening of constipation, urinary retention out of proportion to prostate size, and decreased sweating. He is otherwise healthy with no history of hypertension, diabetes, or Parkinson disease. Because of urinary retention, he was placed on the α1A antagonist tamsulosin, but the fainting spells got worse. Physical examination is unremarkable except for a blood pressure of 167/84 mm Hg supine and 106/55 mm Hg standing. There was an inadequate compensatory increase in heart rate (from 84 to 88 bpm), considering the magnitude of orthostatic hypotension. There is no evidence of peripheral neuropathy or parkinsonian features. Laboratory examinations are negative except for a low plasma norepinephrine (98 pg/mL; normal for his age 250-400 pg/mL). A diagnosis of pure autonomic failure is made, based on the clinical picture and the absence of drugs that could induce orthostatic hypotension and diseases commonly associated with autonomic neuropathy (eg, diabetes, Parkinson disease). What precautions should this patient observe in using sympathomimetic drugs? Can such drugs be used in his treatment?

INTRODUCTION

The sympathetic nervous system is an important regulator of virtually all organ systems. This is particularly evident in the regulation of blood pressure. The sympathetic nervous system is required to maintain blood pressure stable even under relatively minor situations of stress. For example, during standing, the gravitational pooling of blood in the lower body triggers sympathetic stimulation that causes the release of norepinephrine from nerve terminals, which then activates adrenoceptors on postsynaptic sites (see Chapter 6) to restore blood pressure. Also, in response to more stressful situations (eg, hypoglycemia), sympathetic activation causes the adrenal medulla to release epinephrine, which is then transported in the blood to target tissues. In other words, epinephrine acts as a hormone, whereas norepinephrine acts as a neurotransmitter. Both have a role in the "fight or flight" response that characterizes sympathetic activation.

Drugs that mimic the actions of epinephrine or norepinephrine have traditionally been termed sympathomimetic drugs. The sympathomimetics can be grouped by mode of action and by the spectrum of receptors that they activate. Some of these drugs (e.g., norepinephrine and epinephrine) are direct agonists; they directly interact with and activate adrenoceptors. Others are indirect agonists because their actions are dependent on their ability to enhance the actions of endogenous catecholamines by:

Inducing the release of catecholamines by displacing them from adrenergic nerve endings (eg, tyramine, amphetamine)
Inhibiting the reuptake of catecholamines by blocking norepinephrine transporter (NET) (eg, cocaine, tricyclic antidepressants)

I. BASIC PHARMACOLOGY OF SYMPATHOMIMETIC DRUGS

Identification of Adrenoceptors

The identification of adrenoceptors began with classic experiments demonstrating that sympathomimetic amines could be divided into two broad categories based on their pharmacologic profiles. Alpha (α) adrenoceptors were defined by their ability to be stimulated by phenylephrine and blocked by phenoxybenzamine or phentolamine. Beta (β) adrenoceptors respond to isoproterenol and are blocked by propranolol. More recently, the cloning and molecular characterization of adrenoceptors has allowed the division of α and β adrenoceptors into distinct subtypes.

Adrenoceptor Subtypes

Alpha1 (α1) Subtypes: There are three subtypes: α1A, α1B, and α1D. These are all coupled to Gq proteins, which stimulate phospholipase C, leading to increased IP3 and DAG. Specific antagonists include prazosin (non-selective α1), tamsulosin (selective for α1A), and others.

Alpha2 (α2) Subtypes: Three subtypes: α2A, α2B, α2C. All coupled to Gi proteins, which inhibit adenylyl cyclase, decreasing cAMP. Clonidine is the prototype agonist; yohimbine is an antagonist.

Beta (β) Subtypes: Three subtypes: β1, β2, β3. All coupled to Gs proteins, which stimulate adenylyl cyclase, increasing cAMP.

Dopamine Receptors: D1, D2, D3, D4, D5.

TABLE 9-1: Adrenoceptor Types and Subtypes

Receptor	Agonist	Antagonist	G Protein	Effects	Gene Chromosome
α1 type	Phenylephrine	Prazosin	Gq	↑ IP3, DAG	common to all
α1A		Tamsulosin			C8
α1B					C5
α1D					C20
α2 type	Clonidine	Yohimbine	Gi	↓ cAMP	common to all
α2A	Oxymetazoline				C10
α2B		Prazosin			C2
α2C		Prazosin			C4
β type	Isoproterenol	Propranolol	Gs	↑ cAMP	common to all
β1	Dobutamine	Betaxolol			C10
β2	Albuterol	Butoxamine			C5
β3	Mirabegron				C8
Dopamine type	Dopamine
D1	Fenoldopam		Gs	↑ cAMP	C5
D2	Bromocriptine		Gi	↓ cAMP	C11
D3			Gi	↓ cAMP	C3
D4		Clozapine	Gi	↓ cAMP	C11
D5			Gs	↑ cAMP	C4

(Note: An "α1C" receptor was initially described but was later recognized to be identical to the α1A receptor. To avoid confusion, the nomenclature now omits α1C. The adrenoceptors are also known by the abbreviation ADR, followed by the type (ADRA, ADRB) and subtype (ADRA1A, ADRA1B, etc). The corresponding nomenclature for the dopamine receptors is DRD1, DRD2, etc.)

A. Alpha1-Receptor Signaling

Activation of α1 receptors results in the activation of a Gq-G protein, stimulating phospholipase C, and thereby increasing inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 promotes the release of sequestered Ca2+ from the endoplasmic reticulum (ER), and the increase in free intracellular Ca2+ promotes activation of myosin light-chain kinase, smooth muscle contraction, and other responses. Diacylglycerol activates protein kinase C (PKC), which also phosphorylates a number of proteins, including ion channels, resulting in various effects. Activation of α1 receptors also increases the activity of the "Na/H exchanger" (antiporter), causing an intracellular alkalinization.

B. Alpha2-Receptor Signaling

Activation of α2 receptors inhibits adenylyl cyclase activity via coupling to a Gi-protein. Gi-proteins have also been shown to activate inwardly rectifying K+ channels, and to inhibit voltage-regulated Ca2+ channels. Some of the effects of α2 activation are mediated by decreased cAMP, but some are not. Alpha2 agonists, by opening K+ channels, cause hyperpolarization of the cell membrane; by decreasing Ca2+ influx, they decrease neurotransmitter release.

C. Beta-Receptor Signaling

Cyclic AMP is the second messenger that mediates most of the actions of β-receptors. Beta agonists stimulate adenylyl cyclase through coupling with a Gs protein (see Figure 9-2). In the liver, cAMP mediates a cascade of events culminating in the activation of glycogen phosphorylase; in the heart, it increases the influx of calcium across the cell membrane; whereas in smooth muscle it promotes relaxation through phosphorylation of myosin light-chain kinase to an inactive form (see Figure 12-1). Some actions of β adrenoceptors may be mediated through different intracellular signaling pathways, via exchange proteins activated by cAMP rather than conventional protein kinase A (PKA), or via coupling to Gs but independent of cAMP, or coupling to Gq proteins and activation of MAP kinases.

The β3 adrenoceptor is a lower-affinity receptor compared with β1 and β2 receptors but is more resistant to desensitization. It is found in several tissues, but its physiologic or pathologic role in humans is not clear. Beta3 receptors are expressed in the detrusor muscle of the bladder and induce its relaxation, and the selective β3 agonist mirabegron is used clinically for the treatment of symptoms of overactive bladder (urinary urgency and frequency).

D. Dopamine Receptors

The D1 receptor is typically associated with the stimulation of adenylyl cyclase (see Table 9-1); for example, D1 receptor-induced smooth muscle relaxation is presumably due to cAMP accumulation in the smooth muscle of those vascular beds in which dopamine is a vasodilator. The D2 receptor is coupled to Gi proteins, thereby inhibiting adenylyl cyclase, opening K+ channels, and decreasing Ca2+ influx. D3 and D4 receptors also inhibit adenylyl cyclase. The D5 receptor is coupled to Gs and stimulates adenylyl cyclase.

II. CHEMISTRY AND PHARMACOKINETICS OF SYMPATHOMIMETIC DRUGS

Phenylethylamine Derivatives

Sympathomimetic drugs can be viewed as derivatives of phenylethylamine (a phenyl ring with an ethylamine side chain). The endogenous catecholamines (epinephrine, norepinephrine, dopamine) are all catechols (they have -OH groups at the 3 and 4 positions on the benzene ring). The presence of both -OH groups is important for maximal α and β receptor activation.

The absence of one or the other of these groups dramatically reduces the potency of these drugs. For example, phenylephrine (Figure 9-5) is much less potent than epinephrine; its affinity to α receptors is decreased approximately 100-fold, but because its β activity is almost negligible except at very high concentrations, it is a selective α agonist.

On the other hand, the presence of -OH groups makes catecholamines subject to inactivation by catechol-O-methyltransferase (COMT), and because this enzyme is found in the gut and liver, catecholamines are not active orally (see Chapter 6). Absence of one or both -OH groups on the phenyl ring:

Increases bioavailability after oral administration
Prolongs the duration of action
Tends to increase the distribution of the molecule to the CNS (e.g., ephedrine and amphetamine)

Substitutions on the Amine

The nature of alkyl substituents on the amine group affects receptor selectivity. Isoproterenol has a large isopropyl substituent on the nitrogen and is almost a pure β agonist. Albuterol and terbutaline have moderately large substitutions on the amine group and are selective β2 agonists (not absolute selectivity). Dobutamine has a large substituent on the amine group and is relatively selective for β1 receptors.

Alpha-Carbon Substitutions (Position of the Amine Side Chain)

The presence of an alpha-methyl group (as in ephedrine and amphetamine) retards oxidative deamination by MAO, prolongs the duration of action, and enhances CNS penetration. Ephedrine and amphetamine are both resistant to inactivation by MAO and COMT, rely on release of endogenous norepinephrine for at least part of their effects, and have more pronounced CNS effects than most other sympathomimetics.

BOX: Therapeutic Potential of Biased Agonists at Beta Receptors

Traditional β agonists like epinephrine activate cardiac β1 receptors, increasing heart rate and cardiac workload through coupling with G proteins. This can be deleterious in situations such as myocardial infarction. Beta1 receptors are also coupled through G protein-independent signaling pathways involving β-arrestin, which are thought to be cardioprotective. A "biased" agonist could potentially activate only the cardioprotective, β-arrestin-mediated signaling (and not the G protein-mediated signals that lead to greater cardiac workload). Such a biased agonist would be of great therapeutic potential in situations such as myocardial infarction or heart failure. In asthma, there is interest in developing biased agonists that are effective bronchial muscle relaxants but are not subject to desensitization. Biased agonists potent enough to reach these therapeutic goals have not yet been developed.

III. ORGAN SYSTEM EFFECTS OF ADRENOCEPTOR AGONISTS

A. Cardiovascular System

The cardiovascular effects of adrenoceptor agonists depend on the balance of α and β activity, the dose administered, and reflex mechanisms.

Effects of Alpha1-Receptor Activation

Alpha1 stimulation causes vasoconstriction, thereby increasing peripheral vascular resistance and raising blood pressure. The vascular effects of α1 agonists depend on the distribution of α1 receptors in the vasculature, which predominate in the skin, splanchnic vessels, and kidneys. In contrast, blood vessels in skeletal muscle may constrict or dilate depending on whether α or β receptors are activated. The blood vessels of the nasal mucosa express α receptors, and local vasoconstriction induced by sympathomimetics explains their decongestant action.

Effects of Alpha2-Receptor Activation

Selective α2 adrenoceptor agonists, such as clonidine, act in the CNS to reduce sympathetic activity ("central sympatholytics") and are used in the treatment of hypertension (see Chapter 11). Alpha2 adrenoreceptors are also present in the vasculature, and their activation leads to vasoconstriction. This effect, however, is observed only when α2 agonists are given locally, by rapid intravenous injection, or in very high oral doses. When given systemically, these vascular effects are obscured by the central sympatholytic effects of α2 receptors. In patients with pure autonomic failure, characterized by neural degeneration of postganglionic noradrenergic fibers, clonidine may increase blood pressure because the central sympatholytic effects of clonidine become irrelevant whereas the peripheral vasoconstriction remains intact.

Effects of Beta-Receptor Activation

The cardiovascular effects of β-adrenoceptor activation are exemplified by the response to the nonselective β agonist isoproterenol, which activates both β1 and β2 receptors. Stimulation of β receptors in the heart increases cardiac output by increasing contractility and by direct activation of the sinus node to increase heart rate. Beta agonists also decrease peripheral resistance by activating β2 receptors, leading to vasodilation of certain vascular beds (see Table 9-4). The net effect is to maintain or slightly increase systolic pressure and to lower diastolic pressure, so that mean blood pressure is decreased.

The cardiac effects of β agonists are determined largely by β1 receptors (although β2 and α receptors also may be involved, especially in heart failure). The prototypical β1-selective agonist is dobutamine.

Beta1-receptor activation in the heart results in increased calcium influx in cardiac cells with both electrical and mechanical consequences:

In the sinoatrial node: increases pacemaker activity and heart rate (positive chronotropic effect)
In the atrioventricular node: increases conduction velocity (positive dromotropic effect) and decreases the refractory period
In myocardium: increases intrinsic myocardial contractility (positive inotropic effect) and accelerates relaxation

Physiologic stimulation of the heart by catecholamines, therefore, increases heart rate and cardiac output, and it tends to increase coronary blood flow because of coronary vasodilation. Excessive stimulation of ventricular muscle and Purkinje cells can result in ventricular arrhythmias. Expression of β3 adrenoceptors has been detected in the human heart and may be up-regulated in disease states, but the relevance of this finding is not clear.

Effects of Dopamine-Receptor Activation

Intravenous administration of dopamine promotes vasodilation of renal, splanchnic, coronary, cerebral, and perhaps other resistance vessels, via activation of D1 receptors. Activation of the D1 receptor in the renal tubule inhibits Na+/K+-ATPase and reduces sodium reabsorption, thereby increasing natriuresis. At intermediate doses, dopamine stimulates cardiac β1 receptors (positive inotropic and chronotropic effects). At high doses, dopamine activates α1 receptors, causing vasoconstriction.

B. Non-Vascular Smooth Muscle

Bronchi: Beta2 agonists promote bronchodilation, which is their primary therapeutic use in asthma and COPD. Alpha1 agonists cause bronchoconstriction.

Uterus: Beta2 agonists relax uterine smooth muscle (tocolytic effect). This has been used to suppress premature labor, although use is now limited due to adverse effects.

GI tract: Sympathomimetics reduce GI tone and motility, mediated by both α and β receptors.

Bladder: Alpha1 agonists cause contraction of the trigone, sphincter, and capsule of the prostate. Beta3 agonists (mirabegron) relax the detrusor, and are used in overactive bladder.

C. Eye

Mydriasis (pupil dilation): Alpha1 agonists stimulate the radial muscle of the iris, causing pupil dilation (mydriasis) without loss of accommodation. This is distinct from the mydriasis produced by antimuscarinic drugs, which also cause cycloplegia.

Intraocular Pressure: Alpha2 agonists (apraclonidine, brimonidine) reduce intraocular pressure by reducing aqueous humor formation, and are used in glaucoma.

D. CNS

Indirectly acting drugs that enter the CNS (ephedrine, amphetamine, methamphetamine) produce stimulant effects including increased alertness, reduced fatigue, decreased appetite, and elation. These effects are mediated by increased release of catecholamines and dopamine in CNS pathways.

E. Metabolic Effects

Catecholamines stimulate:

Glycogenolysis in liver and skeletal muscle (primarily β2)
Gluconeogenesis (β2)
Lipolysis in adipose tissue (β3, β1)
Insulin secretion is inhibited by α2 receptor activation and stimulated by β2 activation

IV. SPECIFIC SYMPATHOMIMETIC DRUGS

A. Direct-Acting Catecholamines

Epinephrine (Adrenaline)

Epinephrine activates all adrenoceptors (α1, α2, β1, β2, β3). Its cardiovascular effects depend on the dose:

Low doses: β2-mediated vasodilation predominates; systolic BP slightly increased, diastolic BP decreased
High doses: α-mediated vasoconstriction predominates; both systolic and diastolic BP increase

Epinephrine is the drug of choice for anaphylaxis. It is used in cardiac arrest (IV/IO), added to local anesthetics to prolong their action, as a bronchodilator (though largely replaced by selective β2 agonists), and as a topical vasoconstrictor.

Norepinephrine (Levarterenol)

Norepinephrine activates α1, α2, and β1 receptors but has little β2 activity. It causes intense vasoconstriction (α1 activation) in most vascular beds. Due to the baroreceptor reflex compensating for the rise in blood pressure, heart rate may actually decrease (reflex bradycardia) even though norepinephrine directly stimulates β1. It is used as a vasopressor in shock states (septic shock, distributive shock).

Dopamine

Dopamine has a complex pharmacologic profile that is dose-dependent:

Low doses (0.5-2 mcg/kg/min): Primarily D1 receptor activation → renal and mesenteric vasodilation
Intermediate doses (2-10 mcg/kg/min): β1 receptor activation → positive inotropic and chronotropic effects
High doses (>10 mcg/kg/min): α1 receptor activation → vasoconstriction

Dopamine is used in the management of shock, particularly cardiogenic shock with hypotension. Its use in "renal protection" (low-dose) has not been validated in clinical trials.

Dobutamine

Dobutamine is a synthetic catecholamine that is a relatively selective β1 agonist. It increases myocardial contractility (positive inotropic) with less increase in heart rate than isoproterenol. Dobutamine is used for short-term management of cardiogenic shock and acute heart failure as an inotropic agent.

Isoproterenol

Isoproterenol is a non-selective β1 and β2 agonist with very little α activity. It produces marked increases in heart rate (positive chronotropic) and cardiac output, and dilates bronchi and blood vessels. It can cause tachycardia and arrhythmias. Its main use is for temporary control of complete heart block while waiting for a pacemaker, and in bronchospasm.

B. Non-Catecholamine Sympathomimetics

Phenylephrine

Phenylephrine is a selective α1 agonist (structurally similar to epinephrine but lacks the 4-OH on the ring, making it not a catechol). It causes vasoconstriction, increases blood pressure, and causes reflex bradycardia. Due to lack of β activity, it does not stimulate the heart directly. It is used:

As a nasal decongestant (topical)
For treatment of acute hypotension (IV)
As a mydriatic (eye drops)
To raise blood pressure during spinal anesthesia

Oxymetazoline

Oxymetazoline is an α2A agonist used topically as a nasal decongestant and for conjunctival redness. Prolonged use (>3 days) causes rhinitis medicamentosa (rebound nasal congestion).

Clonidine and Related α2 Agonists

Clonidine acts centrally to decrease sympathetic outflow, used primarily as an antihypertensive. Other uses:

Diarrhea in diabetics with autonomic neuropathy
Diminishing craving for narcotics and alcohol during withdrawal
Facilitate cessation of cigarette smoking
Diminish menopausal hot flushes
Pre-medication before anesthesia

Dexmedetomidine is an α2 agonist used for sedation under intensive care circumstances and during anesthesia. It blunts the sympathetic response to surgery, lowers opioid requirements for pain control, and does not depress ventilation.

Tizanidine is an α2 agonist used as a "central muscle relaxant" (see Chapter 27), but many physicians are not aware of its cardiovascular actions, which may lead to unanticipated adverse effects such as orthostatic hypotension followed by rebound hypertension.

Apraclonidine and brimonidine are used topically in glaucoma to reduce intraocular pressure.

Midodrine

Midodrine is an oral α1 agonist (prodrug). It is used for treatment of orthostatic hypotension. Toxicity includes supine hypertension, piloerection (goose bumps), and urinary retention.

Ephedrine

Ephedrine is a mixed agonist - it both directly activates adrenoceptors and releases norepinephrine from nerve terminals. It is resistant to metabolism by MAO and COMT, and has a longer duration of action than catecholamines. Its ability to penetrate the CNS makes it a CNS stimulant. It is used as a pressor agent in spinal/epidural anesthesia. Tachyphylaxis (diminishing response with repeated doses) occurs because of depletion of norepinephrine stores from nerve terminals.

Albuterol (Salbutamol)

Albuterol is a selective β2 agonist used primarily as a bronchodilator in asthma. It is administered by inhalation for rapid onset. Duration of action: 4-6 hours. Toxicity: tremor, tachycardia. Long-acting β2 agonists (LABAs) include salmeterol and formoterol (12-hour duration); ultralong-acting agent indacaterol (24 hours).

Other β2 Agonists

Terbutaline: used subcutaneously for severe acute asthma and as a tocolytic
Ritodrine: tocolytic (now rarely used due to adverse effects)
Salmeterol, Formoterol: LABAs, used as add-on therapy in persistent asthma and COPD

Mirabegron

Mirabegron is a selective β3 agonist used for treatment of overactive bladder (urinary urgency and frequency). It relaxes the detrusor muscle.

V. INDIRECT-ACTING SYMPATHOMIMETICS

Indirect-acting sympathomimetics enhance adrenergic transmission without directly activating adrenoceptors. They work by two major mechanisms:

Releasing stored catecholamines from nerve terminals ("displacers")
Inhibiting reuptake of released transmitter by interfering with NET

A. Amphetamine-Like Drugs

Amphetamine is a racemic mixture of phenylisopropylamine that is important chiefly because of its use and misuse as a CNS stimulant (see Chapter 32). Pharmacokinetically, it is similar to ephedrine; however, amphetamine enters the CNS even more readily, where it has marked stimulant effects on mood and alertness and a depressant effect on appetite. Its d-isomer is more potent than the l-isomer. Amphetamine's actions are mediated through the release of norepinephrine and, to some extent, dopamine.

Methamphetamine (N-methylamphetamine) is very similar to amphetamine, with an even higher ratio of central to peripheral actions.

Methylphenidate is an amphetamine variant whose major pharmacologic effects and abuse potential are similar to those of amphetamine. Methylphenidate may be effective in children with attention deficit hyperactivity disorder (ADHD). Slow or continuous-release preparations of methylphenidate may simplify dosing regimens and increase adherence to therapy, especially in school-age children.

Modafinil and armodafinil are psychostimulants that differ from amphetamine in structure, neurochemical profile, and behavioral effects. Their mechanism of action is not fully known. They inhibit both norepinephrine and dopamine transporters, and increase synaptic concentrations not only of norepinephrine and dopamine, but also of serotonin and glutamate, while decreasing γ-aminobutyric acid (GABA) levels. They are used primarily to improve wakefulness in narcolepsy and some other conditions. Their use can be associated with increases in blood pressure and heart rate, although these are usually mild.

Tyramine (see Figure 6-5) is a normal byproduct of tyrosine metabolism in the body. It is an indirect sympathomimetic, inducing the release of catecholamines from noradrenergic neurons. Tyramine can be produced in high concentrations in protein-rich foods by decarboxylation of tyrosine during fermentation (Table 9-5) but is normally inactive when taken orally because it is readily metabolized by MAO in the liver (ie, low bioavailability because of a very high first-pass effect). In patients treated with MAO inhibitors - particularly inhibitors of the MAO-A isoform - the sympathomimetic effect of tyramine may be greatly intensified, leading to marked increases in blood pressure. This occurs because of increased bioavailability of tyramine and increased neuronal stores of catecholamines. Patients taking MAO inhibitors should avoid tyramine-containing foods (aged cheese, cured meats, and pickled food). There are differences in the effects of various MAO inhibitors on tyramine bioavailability, and isoform-specific or reversible enzyme antagonists may be safer (see Chapters 28 and 30).

B. Catecholamine Reuptake Inhibitors

Many inhibitors of the amine transporters for norepinephrine, dopamine, and serotonin are used clinically. Although specificity is not absolute, some are highly selective for one of the transporters. Many antidepressants - both the tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) - act by blocking reuptake at monoamine transporters.

Cocaine is a unique local anesthetic that also blocks the NET, thereby potentiating norepinephrine at sympathetic synapses and producing peripheral sympathomimetic effects (vasoconstriction, tachycardia, hypertension). Cocaine's psychostimulant effects result from inhibition of dopamine reuptake in the CNS.

Atomoxetine is a selective norepinephrine reuptake inhibitor (NRI) used in the treatment of ADHD.

VI. PHARMACOLOGICAL TARGETING OF MONOAMINE TRANSPORTERS (Figure 9-3)

Panel A: Normal reuptake of norepinephrine (NE) back into the noradrenergic neuron via the norepinephrine transporter (NET), where a proportion is sequestered in presynaptic vesicles through the vesicular monoamine transporter (VMAT).

Panel B (Amphetamine): Amphetamine reverses NET transport, causing release of NE from the cytoplasm into the synaptic cleft (reversed transport).

Panel C (Cocaine): Cocaine blocks NET, preventing reuptake of NE from the synapse.

VII. THERAPEUTIC USES OF SYMPATHOMIMETIC DRUGS

Cardiovascular Uses

1. Anaphylactic Shock and Anaphylaxis Epinephrine is the drug of choice for anaphylaxis. It reverses hypotension, bronchoconstriction, and angioedema. The dose is 0.3-0.5 mg IM (or IV in severe cases).

2. Cardiogenic Shock and Acute Heart Failure

Dobutamine (β1 selective) is the preferred inotrope for cardiogenic shock and acute decompensated heart failure
Dopamine (at intermediate doses) provides additional inotropic support and renal vasodilation
Norepinephrine is used in distributive shock (septic shock) to restore systemic vascular resistance

3. Cardiac Arrest Epinephrine (1 mg IV every 3-5 minutes) is used in cardiac arrest to restore cardiac rhythm and maintain cerebral and coronary perfusion.

4. Orthostatic Hypotension

Midodrine (oral α1 agonist) is the primary treatment
Droxidopa (oral prodrug of norepinephrine) is approved for neurogenic orthostatic hypotension
Fludrocortisone (mineralocorticoid) is also used
Sympathomimetics must be used with great caution in patients like our case study patient (pure autonomic failure) because their denervated blood vessels show supersensitivity to direct-acting catecholamines, so even small doses can cause marked hypertension

5. Hypertension Urgency/Emergency Clonidine (oral) can be used for urgent blood pressure reduction.

6. Local Anesthesia Epinephrine is added to local anesthetic solutions to produce vasoconstriction at the injection site, reducing systemic absorption of the anesthetic and prolonging the anesthetic effect.

7. Vasopressors During Spinal Anesthesia Phenylephrine or ephedrine is used to counteract the hypotension that commonly follows spinal or epidural anesthesia.

Pulmonary Uses

Asthma and COPD:

Short-acting β2 agonists (SABAs): Albuterol by inhalation for acute bronchospasm
Long-acting β2 agonists (LABAs): Salmeterol, formoterol - add-on maintenance therapy
Ultra-long-acting: Indacaterol

Ophthalmologic Uses

Phenylephrine (topical): mydriasis for fundus examination
Apraclonidine, brimonidine (topical): reduce intraocular pressure in glaucoma
Oxymetazoline (topical): reduce conjunctival redness

Nasal Decongestants

Phenylephrine, oxymetazoline (topical): nasal decongestants by vasoconstriction of nasal mucosal vessels
Oral decongestants: pseudoephedrine (α1 agonist)

CNS Uses

ADHD:

Methylphenidate (dopamine and norepinephrine reuptake inhibitor)
Amphetamine/dextroamphetamine (indirect sympathomimetic)
Atomoxetine (selective NRI)
Slow/continuous-release preparations of clonidine and guanfacine (α2 agonists)
Clinical trials suggest modafinil may be useful in ADHD, but FDA approval has not been granted for children

Narcolepsy:

Modafinil, armodafinil (promote wakefulness)

Obesity:

Amphetamine-like drugs were used but are no longer recommended due to abuse potential and cardiovascular adverse effects

Uterine Uses

Premature Labor (Tocolysis):

Beta2 agonists (terbutaline, ritodrine) relax uterine smooth muscle
Use is limited because of adverse cardiovascular effects in the mother

Other Uses of α2 Agonists

Clonidine: diarrhea in diabetics with autonomic neuropathy; opioid/alcohol withdrawal; smoking cessation; menopausal hot flushes
Dexmedetomidine: ICU sedation, procedural sedation, anesthesia adjunct
Tizanidine: central muscle relaxant

VIII. APPLICATION OF BASIC PHARMACOLOGY TO A CLINICAL PROBLEM: HORNER SYNDROME

Horner syndrome is a condition - usually unilateral - that results from interruption of the sympathetic nerves to the face. This translates clinically with vasodilation, ptosis, miosis, and loss of sweating on the affected side. The syndrome can be caused by either a preganglionic or a postganglionic lesion, and knowledge of the location of the lesion (preganglionic or postganglionic) helps determine the optimal therapy.

A localized lesion in a nerve causes degeneration of the distal portion of that fiber and loss of transmitter contents from the degenerated nerve ending - without affecting neurons innervated by the fiber. Therefore, a preganglionic lesion leaves the postganglionic adrenergic neuron intact, whereas a postganglionic lesion results in degeneration of the adrenergic nerve endings and loss of stored catecholamines from them. Because indirectly acting sympathomimetics require normal stores of catecholamines, such drugs can be used to test for the presence of normal adrenergic nerve endings. The iris, because it is easily visible and responsive to topical sympathomimetics, is a convenient assay tissue in the patient.

If the lesion of Horner syndrome is postganglionic, indirectly acting sympathomimetics (e.g., cocaine, hydroxyamphetamine) will not dilate the abnormally constricted pupil because catecholamines have been lost from the nerve endings in the iris. In contrast, the pupil dilates in response to phenylephrine, which acts directly on the α receptors on the smooth muscle of the iris.
A patient with a preganglionic lesion, on the other hand, shows a normal response to both drugs, since the postganglionic fibers and their catecholamine stores remain intact in this situation.

IX. SUMMARY TABLE: Sympathomimetic Drugs

Subclass, Drug	Mechanism of Action	Effects	Clinical Applications	Pharmacokinetics, Toxicities, Interactions
α1 AGONISTS
Midodrine	Activates phospholipase C, resulting in increased intracellular calcium and vasoconstriction	Vascular smooth muscle contraction increasing BP	Orthostatic hypotension	Oral; prodrug converted to active drug with a 1-h peak effect. Toxicity: Supine hypertension, piloerection (goose bumps), and urinary retention
Phenylephrine	(same mechanism)	Same	Acute hypotension (IV), nasal decongestant (intranasal)
α2 AGONISTS
Clonidine	Inhibits adenylyl cyclase and interacts with other intracellular pathways	Vasoconstriction is masked by central sympatholytic effect, which lowers BP	Hypertension	Oral; transdermal; peak effect 1-3 h; t1/2 of oral drug ~12 h; produces dry mouth and sedation
α-Methyldopa, guanfacine, guanabenz	(same class)	Same	Also used as central sympatholytics
Dexmedetomidine		Prominent sedative effects	Used in anesthesia
Tizanidine			Used as a muscle relaxant
Apraclonidine, brimonidine			Used topically in glaucoma to reduce intraocular pressure
β1 AGONISTS
Dobutamine	Activates adenylyl cyclase, increasing myocardial contractility	Positive inotropic effect	Cardiogenic shock, acute heart failure	IV; requires dose titration to desired effect
β2 AGONISTS
Albuterol	Activates adenylyl cyclase	Bronchial smooth muscle dilation	Asthma	Inhalation; duration 4-6 h. Toxicity: Tremor, tachycardia
Salmeterol, formoterol	Same	Same	LABA, asthma and COPD	Duration ~12 h
Indacaterol	Same	Same	COPD	Duration ~24 h
Terbutaline, ritodrine	Same	Uterine relaxation	Premature labor (tocolysis)	Subcut; IV
β3 AGONISTS
Mirabegron	Activates adenylyl cyclase	Detrusor muscle relaxation	Overactive bladder	Oral
NON-SELECTIVE β AGONISTS
Isoproterenol	Activates β1 and β2 receptors	↑ heart rate and contractility; bronchodilation	Heart block (temporary), bronchospasm	IV; inhalation. Toxicity: Tachycardia, arrhythmias
CATECHOLAMINES (mixed)
Epinephrine	Activates all adrenoceptors	Vasoconstriction (high dose), vasodilation (low dose), bronchodilation, ↑ heart rate and contractility	Anaphylaxis, cardiac arrest, local anesthesia adjunct, bronchospasm	IV, IM, SC, inhalation, topical. Toxicity: Hypertension, arrhythmias, anxiety, tremor
Norepinephrine	Activates α1, α2, β1 (not β2)	Vasoconstriction, ↑ BP; reflex bradycardia	Vasopressor in septic/distributive shock	IV infusion. Toxicity: Severe hypertension, tissue ischemia (extravasation)
Dopamine	D1, β1, α1 (dose dependent)	Dose-dependent effects: renal vasodilation → inotropic → vasoconstriction	Cardiogenic shock, hypotension	IV infusion
INDIRECT AGONISTS
Amphetamine	Releases norepinephrine and dopamine from nerve terminals	CNS stimulation, ↑ BP, ↑ HR	ADHD, narcolepsy	Oral; high CNS penetration. High abuse potential
Methylphenidate	Dopamine and NE reuptake inhibition	Similar to amphetamine	ADHD	Oral; multiple formulations
Atomoxetine	Selective NE reuptake inhibitor	↑ NE at synapse	ADHD	Oral; non-stimulant
Cocaine	Blocks NET; local anesthetic	Vasoconstriction, tachycardia; CNS stimulation	Topical local anesthetic for ENT	Topical. High abuse potential
Tyramine	Releases NE from nerve terminals	↑ BP	None (food byproduct)	MAO inhibitors greatly potentiate its effects
Modafinil	Inhibits NE and dopamine transporters	Promotes wakefulness	Narcolepsy; possibly ADHD	Oral. Toxicity: Mild ↑ BP and HR

CASE STUDY RESOLUTION

The patient has pure autonomic failure with degeneration of postganglionic noradrenergic fibers. His low plasma norepinephrine confirms the loss of sympathetic tone. Key considerations:

Denervation supersensitivity: Because postganglionic adrenergic fibers are degenerated, his blood vessels and heart have upregulated adrenoceptors. Therefore, even small doses of direct-acting sympathomimetics (epinephrine, norepinephrine, phenylephrine) can cause exaggerated, dangerous responses (severe hypertension).
Indirect-acting drugs are not effective: Drugs that rely on releasing endogenous norepinephrine from nerve endings (amphetamine, tyramine) will be ineffective because the nerve endings are depleted/degenerated.
Treatment: The drug of choice for his orthostatic hypotension is midodrine (an oral α1 agonist), used with extreme caution given supersensitivity. Non-pharmacologic measures (compression stockings, head-of-bed elevation, liberal salt intake) are first line. The patient must avoid supine position after taking midodrine to prevent severe hypertension.
Tamsulosin worsened symptoms because it is an α1A antagonist that blocks the remaining α1-mediated vasoconstriction, further reducing the already compromised sympathetic vascular tone.

Katzung's Basic and Clinical Pharmacology, 16th Edition - Chapter 9: Adrenoceptor Agonists & Sympathomimetic Drugs, pp. 142-160

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