Adrenergic agonists and antagonists produce their clinical effects by interacting with the adrenergic receptors (ie, adrenoceptors). The clinical effects of these drugs can be deduced from an understanding of the adrenoceptor physiology and a knowledge of which receptors each drug activates or blocks.
The term “adrenergic” originally referred to the effects of epinephrine (adrenaline), although norepinephrine (noradrenaline) is the primary neurotransmitter responsible for most of the adrenergic activity of the sympathetic nervous system. With the exception of eccrine sweat glands and some blood vessels, norepinephrine is released by postganglionic sympathetic fibers at end-organ tissues (Figure 14-1). In contrast, acetylcholine is released by preganglionic sympathetic fibers and all parasympathetic fibers.
The sympathetic nervous system. Organ innervation, receptor type, and response to stimulation. The origin of the sympathetic chain is the thoracoabdominal (T1-L3) spinal cord, in contrast to the craniosacral distribution of the parasympathetic nervous system. Another anatomic difference is the greater distance from the sympathetic ganglion to the visceral structures.
Norepinephrine is synthesized in the cytoplasm of sympathetic postganglionic nerve endings and stored in the vesicles (Figure 14-2). After release by a process of exocytosis, the action of norepinephrine is primarily terminated by reuptake into the postganglionic nerve ending (inhibited by tricyclic antidepressants), but also by diffusion from receptor sites, or via metabolism by monoamine oxidase (inhibited by monoamine oxidase inhibitors) and catechol-O-methyltransferase (Figure 14-3). Prolonged adrenergic activation leads to desensitization and hyporesponsiveness to further stimulation.
Sequential metabolism of norepinephrine and epinephrine. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) produce a common end product, vanillylmandelic acid (VMA).
Adrenergic receptors are divided into two general categories: α and β. Each of these has been further subdivided into at least two subtypes: α1 and α2, and β1, β2, and β3. The α-receptors have been further divided using molecular cloning techniques into α1A, α1B, α1D, α2A, α2B, and α2C. These receptors are linked to G proteins (Figure 14-4; Drs. Rodbell and Gilman received the Nobel Prize in physiology or medicine in 1994 for their discovery)—heterotrimeric receptors with α, β, and γ subunits. The different adrenoceptors are linked to specific G proteins, each with a unique effector, but each using guanosine triphosphate (GTP) as a cofactor. α1 is linked to Gq, which activates phospholipases; α2 is linked to Gi, which inhibits adenylate cyclase, and β is linked to Gs, which activates adenylate cyclase.
The adrenoceptor is a transmembrane-spanning receptor made up of seven subunits, which is linked to a G protein. G proteins are trimeric endoplasmic membrane proteins made of α, β, and γ units. With activation, GTP on the α-subunit is replaced by GDP, stimulating a conformational change, disassociating the α, β, and γ units. Either the Gα or Gβγ subunits can activate (or inhibit) the enzyme effector for that adrenoceptor. M1-M7, membrane-spanning units; α, β, γ, subunits of G protein; GTP, guanosine triphosphate; Pi, inorganic phosphate—quickly assimilated; GDP, guanosine diphosphate; E, effector; cyclophosphatase for Gq, adenylate cyclase for Gi, and Gs.
α1-Receptors are postsynaptic adrenoceptors located in smooth muscle throughout the body (in the eye, lung, blood vessels, uterus, gut, and genitourinary system). Activation of these receptors increases intracellular calcium ion concentration, which leads to contraction of smooth muscles. Thus, α1-agonists are associated with mydriasis (pupillary dilation due to contraction of the radial eye muscles), bronchoconstriction, vasoconstriction, uterine contraction, and constriction of sphincters in the gastrointestinal and genitourinary tracts. α1-stimulation also inhibits insulin secretion and lipolysis. The myocardium possesses α1-receptors that have a positive inotropic effect, which might play a role in catecholamine-induced arrhythmia. During myocardial ischemia, enhanced α1-receptor coupling with agonists is observed. Nonetheless, the most important cardiovascular effect of α1-stimulation is vasoconstriction, which increases peripheral vascular resistance, left ventricular afterload, and arterial blood pressure.
In contrast to α1-receptors, α2-receptors are located primarily on the presynaptic nerve terminals. Activation of these adrenoceptors inhibits adenylate cyclase activity. This decreases the entry of calcium ions into the neuronal terminal, which limits subsequent exocytosis of storage vesicles containing norepinephrine. Thus, α2-receptors create a negative feedback loop that inhibits further norepinephrine release from the neuron. In addition, vascular smooth muscle contains postsynaptic α2-receptors that produce vasoconstriction. More importantly, stimulation of postsynaptic α2-receptors in the central nervous system causes sedation and reduces sympathetic outflow, which leads to peripheral vasodilation and lower blood pressure.
β-Adrenergic receptors are classified into β1, β2, and β3 receptors. The catecholamines, norepinephrine, and epinephrine are equipotent on β1 receptors, but epinephrine is significantly more potent than norepinephrine on β2 receptors.
The most important β1-receptors are located on the postsynaptic membranes in the heart. Stimulation of these receptors activates adenylate cyclase, which converts adenosine triphosphate to cyclic adenosine monophosphate and initiates a kinase phosphorylation cascade. Initiation of the cascade has positive chronotropic (increased heart rate), dromotropic (increased conduction), and inotropic (increased contractility) effects.
β2-Receptors are primarily postsynaptic adrenoceptors located in smooth muscle and gland cells. They share a common mechanism of action with β1-receptors: adenylate cyclase activation. Despite this commonality, β2 stimulation relaxes smooth muscle, resulting in bronchodilation, vasodilation, and relaxation of the uterus (tocolysis), bladder, and gut. Glycogenolysis, lipolysis, gluconeogenesis, and insulin release are stimulated by β2-receptor activation. β2-agonists also activate the sodium-potassium pump, which drives potassium intracellularly and can induce hypokalemia and dysrhythmias.
β3-Receptors are found in the gallbladder and brain adipose tissue. Their role in gallbladder physiology is unknown, but they are thought to play a role in lipolysis and thermogenesis in brown fat.
Dopamine (DA) receptors are a group of adrenergic receptors that are activated by dopamine; these receptors are classified as D1 and D2 receptors. Activation of D1 receptors mediates vasodilation in the kidney, intestine, and heart. D2 receptors are believed to play a role in the antiemetic action of droperidol.