Page 155 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 9 Adrenoceptor Agonists & Sympathomimetic Drugs 141

TABLE 9–2 Relative receptor affinities. Many mechanisms have been found to contribute to desensiti-
zation. Some mechanisms occur relatively slowly, over the course
Relative Receptor of hours or days, and these typically involve transcriptional or
Affinities translational changes in the receptor protein level, or its migration
Alpha agonists to the cell surface. Other mechanisms of desensitization occur
Phenylephrine, methoxamine α 1 > α 2 >>>>> β quickly, within minutes. Rapid modulation of receptor function
in desensitized cells may involve critical covalent modification of
Clonidine, methylnorepinephrine α 2 > α 1 >>>>> β
the receptor, especially by phosphorylation of specific amino acid
Mixed alpha and beta agonists
residues, association of these receptors with other proteins, or
Norepinephrine α 1 = α 2 ; β 1 >> β 2 changes in their subcellular location.
Epinephrine α 1 = α 2 ; β 1 = β 2 There are two major categories of desensitization of responses
Beta agonists mediated by G protein-coupled receptors. Homologous desensi-
Dobutamine 1 β 1 > β 2 >>>> α tization refers to loss of responsiveness exclusively of the receptors
that have been exposed to repeated or sustained activation by an
Isoproterenol β 1 = β 2 >>>> α
agonist. Heterologous desensitization refers to the process by
Albuterol, terbutaline, β 2 >> β 1 >>>> α which desensitization of one receptor by its agonists also results
metaproterenol, ritodrine
in desensitization of another receptor that has not been directly
Dopamine agonists
activated by the agonist in question.
Dopamine D 1 = D 2 >> β >> α A major mechanism of desensitization that occurs rap-
Fenoldopam D 1 >> D 2 idly involves phosphorylation of receptors by members of the
1 G protein-coupled receptor kinase (GRK) family, of which
See text.
there are seven members. Specific adrenoceptors become sub-
strates for these kinases only when they are bound to an agonist.
Receptor Selectivity This mechanism is an example of homologous desensitization
because it specifically involves only agonist-occupied receptors.
Examples of clinically useful sympathomimetic agonists that are Phosphorylation of these receptors enhances their affinity for
relatively selective for α -, α -, and β-adrenoceptor subgroups are arrestins, a family of four proteins, of which the two nonvisual
1
2
compared with some nonselective agents in Table 9–2. Selectiv- arrestin subtypes are widely expressed. Upon binding of arrestin,
ity means that a drug may preferentially bind to one subgroup of the capacity of the receptor to activate G proteins is blunted, pre-
receptors at concentrations too low to interact extensively with sumably as a result of steric hindrance (see Figure 2–12). Arrestin
another subgroup. However, selectivity is not usually absolute then interacts with clathrin and clathrin adaptor AP2, leading to
(nearly absolute selectivity has been termed “specificity”), and at endocytosis of the receptor.
higher concentrations, a drug may also interact with related classes In addition to desensitizing agonist responses mediated by
of receptors. The effects of a given drug may depend not only G proteins, arrestins can trigger G protein-independent signal-
on its selectivity to adrenoreceptor types, but also to the relative ing pathways. Recognition that G protein-coupled receptors
expression of receptor subtypes in a given tissue. can signal through both G protein-coupled and G protein-inde-
pendent pathways has raised the concept of developing biased
Receptor Regulation agonists that selectively activate these arrestin-coupled signaling
pathways (see Box: Therapeutic Potential of Biased Agonists at
Responses mediated by adrenoceptors are not fixed and static. Beta Receptors).
The magnitude of the response depends on the number and func- Receptor desensitization may also be mediated by second-
tion of adrenoceptors on the cell surface and on the regulation messenger feedback. For example, β adrenoceptors stimulate
of these receptors by catecholamines themselves, other hormones cAMP accumulation, which leads to activation of protein kinase
and drugs, age, and a number of disease states (see Chapter 2). A; protein kinase A can phosphorylate residues on β receptors,
These changes may modify the magnitude of a tissue’s physiologic resulting in inhibition of receptor function. For the β 2 receptor,
response to catecholamines and can be important clinically dur- protein kinase A phosphorylation occurs on serine residues in the
ing the course of treatment. One of the best-studied examples of third cytoplasmic loop of the receptor. Similarly, activation of
receptor regulation is the desensitization of adrenoceptors that protein kinase C by G q -coupled receptors may lead to phosphory-
may occur after exposure to catecholamines and other sympatho- lation of this class of G protein-coupled receptors. Protein kinase
mimetic drugs. After a cell or tissue has been exposed for a period A phosphorylation of the β receptor also switches its G protein
2
of time to an agonist, that tissue often becomes less responsive to preference from G to G , further reducing cAMP response. This
s
i
further stimulation by that agent (see Figure 2–12). Other terms second-messenger feedback mechanism has been termed heterolo-
such as tolerance, refractoriness, and tachyphylaxis have also been gous desensitization because activated protein kinase A or protein
used to denote desensitization. This process has potential clinical kinase C may phosphorylate any structurally similar receptor
significance because it may limit the therapeutic response to sym- with the appropriate consensus sites for phosphorylation by these
pathomimetic agents. enzymes.