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Chapter: Clinical Anesthesiology: Clinical Pharmacology: Adrenergic Agonists & Antagonists

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Adrenoceptor Physiology

The term “adrenergic” originally referred to the effects of epinephrine (adrenaline), although nor-epinephrine (noradrenaline) is the primary neu-rotransmitter responsible for most of the adrenergic activity of the sympathetic nervous system.

ADRENOCEPTOR PHYSIOLOGY

The term “adrenergic” originally referred to the effects of epinephrine (adrenaline), although nor-epinephrine (noradrenaline) is the primary neu-rotransmitter 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 post-ganglionic sympathetic fibers at end-organ tissues (Figure 14–1). In contrast, acetylcholine is released by preganglionic sympathetic fibers and all para-sympathetic fibers.


Norepinephrine is synthesized in the cyto-plasm of sympathetic postganglionic nerve end-ings and stored in the vesicles (Figure 14–2). After release by a process of exocytosis, the action of norepinephrine is primarily terminated by reup-take into the postganglionic nerve ending (inhib-ited by tricyclic antidepressants), but also by diffusion from receptor sites, or via metabolism by monoamine oxidase (inhibited by monoamine oxidase inhibitors) and catechol-O-methyltransfer-ase (Figure 14–3). Prolonged adrenergic activation leads to desensitization and hyporesponsiveness to further stimulation.


Adrenergic receptors are divided into two gen-eral categories: α and β. Each of these has been fur-ther subdivided into at least two subtypes: α1 and α2, and β1, β2, and β3. The α-receptors have beenfurther 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)—heterotri-meric receptors with α, β, and γ subunits. The differ-ent adrenoceptors are linked to specific G proteins, each with a unique effector, but each using guano-sine 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.


α1-Receptors

α1-Receptors are postsynaptic adrenoceptorslocated in smooth muscle throughout the body (in the eye, lung, blood vessels, uterus, gut, and geni-tourinary system). Activation of these receptors increases intracellular calcium ion concentration, which leads to contraction of smooth muscles. Thus, α1-agonists are associated with mydriasis (pupil-lary 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 andlipolysis. 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 after-load, and arterial blood pressure.

α2-Receptors

In contrast to α1-receptors, α2-receptors are located primarily on the presynaptic nerve termi-nals. 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 cre-ate a negative feedback loop that inhibits further norepinephrine release from the neuron. In addi-tion, vascular smooth muscle contains postsyn-aptic α2-receptors that produce vasoconstriction. More importantly, stimulation of postsynaptic α2-receptors in the central nervous system causessedation and reduces sympathetic outflow, which leads to peripheral vasodilation and lower blood pressure.

β1-Receptors

β-Adrenergic receptors are classified into β1, β2, and β3receptors. The catecholamines, norepinephrine, and epinephrine are equipotent on β1 receptors, but epinephrine is significantly more potent than nor-epinephrine on β2 receptors.The most important β1-receptors are located on the postsynaptic membranes in the heart. Stimulation of these receptors activates adenyl-ate 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 ino-tropic (increased contractility) effects.

β2-Receptors

β2-Receptors are primarily postsynaptic adreno-ceptors located in smooth muscle and gland cells. They share a common mechanism of action with β1-receptors: adenylate cyclase activation. Despitethis 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 activa-tion. β2-agonists also activate the sodium–potassium pump, which drives potassium intracellularly and can induce hypokalemia and dysrhythmias.

β3-Receptors

β3-Receptors are found in the gallbladder and brainadipose tissue. Their role in gallbladder physiology is unknown, but they are thought to play a role in lipolysis and thermogenesis in brown fat.

Dopaminergic Receptors

Dopamine (DA) receptors are a group of adrener-gic receptors that are activated by dopamine; these receptors are classified as D1 and D2 receptors. Acti-vation 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.

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