Drugs that affect adrenergic functions are among the most commonly employed therapeutic agents in medical practice. The adrenergic pharmaceuticals that constitute the therapeutic armamentarium may affect adrenergic receptors, sympathetic nerve endings, or central sympathetic outflow. Most of these agents are congeners of the naturally occurring catecholamines.
Adrenergic agonists are compounds that stimulate adrenergic receptors and produce the characteristic response of the stimulated effector tissue. Adrenergic receptors are considered in detail in Part I.
Therapeutic uses of the naturally occurring catecholamines
Although not extensively used anymore because of their nonselective effects, brief duration of action, and requirement for parenteral administration, the naturally occurring catecholamines do have important therapeutic indications and are lifesaving in some situations (Table 4.1).
The most important use of E is in the treatment of severe allergic reactions, particularly anaphylaxis, where the prompt administration of E is frequently lifesaving. Patients with bee venom allergy or idiopathic anaphylaxis should be instructed in the use of Epi Pens for immediate subcutaneous or intramuscular self-administration upon exposure or at the beginning of an attack. When patients present in shock from anaphylaxis, intravenous (i.v.) E should be administered through a secure i.v. line. It is essential to use the proper dilution as E comes in vials of different strengths. When given by the i.v. route, it should be diluted and administered slowly. The usual dose by this route is about 0.3 to 0.5 mg; the dose can be titrated to the restoration of blood pressure (BP) in patients with severe hypotension. E is the specific antidote for anaphylactic reactions; diphenhydramine (Benadryl) and other antihistamines have a secondary role.
TABLE 4.1 Therapeutic Uses of the Naturally Occurring Catecholamines
Severe hypersensitivity reactions (facial swelling, bronchospasm)
Intravenous or intracardiac
Combination with local anesthetics (prolong duration of action, delay absorption)
Highest dose: ↑ vasoconstriction, ↑ BP (α1 receptors)
DA, dopamine; BP, blood pressure.
E is also used as a cardiac stimulant in cardiac arrests; it may be administered i.v. or via intracardiac injection. Other uses include combination with topical anesthetic agents to delay absorption and prolong the effect, and as a topically applied agent to decrease bleeding.
NE, a potent pressor, is used in the treatment of shock and severe hypotensive reactions. It should be administered through an indwelling i.v. line to avoid extravasation with subsequent necrosis and sloughing of the skin.
Intravenous DA has a range of effects that depend on the concentration achieved in the blood; at low rates of infusion, stimulation of the DA1 receptors results in renal and mesenteric vasodilation and increased sodium excretion, actions that are beneficial in some clinical situations associated with low BP and poor renal perfusion. At higher rates of infusion, it stimulates β1 receptors and exerts a positive inotropic and chronotropic effect on the heart. At further higher concentrations, α1 receptors are stimulated with an increase in vasoconstriction and hence BP. Some of the effects of DA are exerted indirectly by releasing NE from SNS terminals. These actions make DA a potentially useful agent in the treatment of hypotensive oliguric states such as congestive heart failure (CHF), hepatorenal syndrome, and shock.
Congeners of the naturally occurring catecholamines that stimulate adrenergic receptors are referred to as sympathomimetic amines because they mimic, in some respects, the actions of endogenous catecholamines or the effects of SNS stimulation (Tables 4.2 and 4.3). The basic parent compound is phenylethylamine with the carbon atoms designated as shown in Figure 1.1. The structure-activity relationships for sympathomimetic amines have been well established: substitutions and deletions at various sites account for the different patterns of activity, receptor subtype selectivity, oral bioavailability, differences in metabolism, prolongation of action, and for central nervous system (CNS) penetration, as compared with the naturally occurring catecholamines and with each other. A few salient points about the synthetic molecular modifications include the following: (1) metabolism is altered and the duration of action prolonged by modifications of the catechol structure (blocks metabolism by catechol O-methyltransferase) and by substitutions on the α carbon of the side chain (blocks metabolism by monoamine oxidase [MAO]); (2) absence of a polar (hydroxyl) group on the β carbon of the side chain increases lipid solubility and CNS penetration; and (3) substitution of alkyl groups for hydrogen on the amino nitrogen conveys β receptor (particularly β2) activity.
TABLE 4.3 Indirect and Mixed Acting Sympathomimetic Amines
Ephedrine (oral) (direct + indirect)
CV and CNS stimulation; Bronchodilation
Amphetamine (oral) (indirect)
CNS and CV stimulation; Appetite suppressant
Rarely prescribed; ADHD; narcolepsy; obesity
Methylphenidate (oral) (Indirect)
CV, cardiovascular; CNS, central nervous system; ADHD, attention deficit/hyperactivity disorder.
Direct and indirect acting sympathomimetic amines
Sympathomimetic amines may also be classified as direct or indirect acting: the direct acting compounds stimulate adrenergic receptors, whereas the indirect acting amines release NE from the neurotransmitter stores in the sympathetic nerve endings. Indirect acting sympathomimetic amines are substrates for the amine uptake process of the SNS endings; once they gain access to the nerve ending, they may release NE from storage sites in the granules of the nerve terminals, thereby generating a sympathomimetic effect. These indirect acting amines may also block NE reuptake into the nerve ending, thus potentiating the adrenergic response. Tyramine is the prototypical indirect acting amine, whereas phenylephrine is the prototypical direct acting α1 agonist. Many sympathomimetic amines exhibit both direct and indirect effects. Because they release NE, indirect acting sympathomimetic amines have both α and β effects.
Some indirect acting amines may be stored in the sympathetic granules and released in response to sympathetic nerve impulses. As these amines are less potent than the endogenous neurotransmitter NE, the subsequent effector response is diminished. These compounds are referred to as “false transmitters.”
α Adrenergic agonists
Many sympathetic amines have been developed with substantial selectivity for the α or β receptor as well as for the various subtypes of both groups. The second messengers and intracellular cascades in effector tissues are considered in Part I.
Selective α1 receptor agonists and their therapeutic applications
Phenylephrine causes smooth muscle contraction including, most importantly, vasoconstriction; it is used as a nasal decongestant, for pupillary dilatation, and as a vasopressor. Although there is an oral formulation that has been marketed as an alternative to pseudoephedrine, its effectiveness by the oral route has been questioned; its major use as a decongestant for colds and allergies is as a nasal spray. It is particularly useful as an i.v. pressor agent for hypotension induced by spinal anesthesia, and may be useful for the treatment of hypotension associated with sepsis as well. In patients with paroxysmal atrial tachycardia, it has been used to elevate BP as a means of sharply increasing vagal tone in order to convert back to sinus rhythm.
Oxymetazoline is an imidazoline derivative utilized as a locally applied direct acting α1 agonist that causes vasoconstriction; it is used as a decongestant in nasal sprays for symptomatic relief of allergies, upper respiratory infections, and sinus congestion. In topical ophthalmic preparations, it is used for allergic conjunctivitis. Other imidazoline derivatives are also available for similar topical usage.
Midodrine, a prodrug that forms the active metabolite desglymidodrine, is a selective α1 agonist that causes vasoconstriction of the arterial and venous vascular beds. It is active after oral ingestion and has a duration of action of 4 to 6 hours. It is used in the treatment of orthostatic hypotension but its efficacy is limited by supine hypertension and venoconstriction, which diminishes the reservoir in the capacitance vessels, an effect that may worsen the orthostatic fall in BP. It is frequently employed in cirrhotic patients with low BP, oliguria, and impending hepatorenal syndrome, again with limited efficacy.
Droxidopa (L-dihydroxyphenylserine, L-DOPS), although not a selective α1 inhibitor, is another prodrug used in the treatment of orthostatic hypotension. A synthetic amino acid precursor of NE, droxidopa is decarboxylated by L-aromatic amino acid decarboxylase to form NE in vivo. The NE so formed functions as a circulating vasopressor rather than as a neurotransmitter. It is administered orally and has a duration of action of about 4 to 6 hours. It increases BP in the sitting and standing positions without an increase in heart rate. The supine position must be avoided to prevent severe hypertension (black box warning). Use of this drug requires supervision and it is not established that efficacy is retained after long-term usage. Like all treatment for neurogenic orthostatic hypotension, it is less than satisfactory as it does not restore the normal relationship between changes in position and SNS activity. It may, nonetheless, provide symptomatic improvement in some patients.
Selective α2 receptor agonists and their therapeutic applications
Clonidine, a centrally acting α2 agonist, diminishes central sympathetic outflow via an inhibitory effect on brainstem sympathetic centers, thereby lowering BP. Its major use is in the treatment of hypertension. It is active orally and also available as a transdermal patch that releases active compound over a period of 1 week. Clonidine has been used in the treatment of addictions where it may ameliorate withdrawal symptoms in patients addicted to narcotics, alcohol, and benzodiazepines. The usefulness of clonidine is limited by a host of adverse effects, many reflective of its actions on the CNS. These include drowsiness, fatigue, dry mouth, vivid dreams and nightmares, and hallucinations. Abrupt withdrawal of clonidine may result in reflexive SNS discharge with a hypertensive paroxysm, so discontinuation of clonidine should be gradual rather than abrupt.