DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

194 and inhibition of excitable membranes. These are most
clear in myocardium, where inhibition of adenylyl
cyclase and activation of K + conductances account for
the negative inotropic and chronotropic effects of ACh.
The specificity is not absolute, however, and depends on
proper trafficking of the G protein subunits within the
cell; consequently, heterologous systems may exhibit
alternative interactions between mAChRs and G–protein
coupled pathways (Nathanson, 2008). In addition, there
are numerous reports suggesting the differential subcellular
location of specific mAChR subtypes in a variety
of cell types in the nervous system and in a variety of
non-neuronal polarized cells.
SECTION II
NEUROPHARMACOLOGY
Following activation by classical or allosteric agonists,
mAChRs can be phosphorylated by a variety of receptor kinases and
second-messenger regulated kinases; the phosphorylated mAChR
subtypes then can interact with β-arrestin and possibly other adaptor
proteins. As a result, mAChR signaling pathways may be differentially
altered. Agonist activation of mAChRs also may induce
receptor internalization and down-regulation (van Koppen and
Kaiser, 2003). Muscarinic AChRs can also regulate other signal
transduction pathways that have diverse effects on cell growth, survival,
and physiology, such as the MAP kinase, phosphoinositide-3-kinase,
RhoA, and Rac1 (Nathanson, 2008).
Changes in mAChR levels and activity have been implicated in
the pathophysiology of numerous major diseases in the CNS and in the
autonomic nervous system (Table 8–3). Phenotypic analysis of
mAChR-mutant mice as well as the development of selective agonists
and antagonists has led to a wealth of new information regarding the
physiological and potential pathophysiological roles of the individual
mAChR subtype (Langmead et al., 2008; Wess et al., 2007).
Adrenergic Transmission
Under this general heading are norepinephrine (NE), the
principal transmitter of most sympathetic postganglionic
fibers and of certain tracts in the CNS; dopamine (DA),
the predominant transmitter of the mammalian
extrapyramidal system and of several mesocortical and
mesolimbic neuronal pathways; and epinephrine, the
major hormone of the adrenal medulla. Collectively,
these three amines are called catecholamines.
A tremendous amount of information about catecholamines
and related compounds has accumulated in
recent years partly because of the importance of interactions
between the endogenous catecholamines and
many of the drugs used in the treatment of hypertension,
mental disorders, and a variety of other conditions.
The details of these interactions and of the
pharmacology of the sympathomimetic amines themselves
will be found in subsequent chapters. The basic
physiological, biochemical, and pharmacological features
are presented here.
Synthesis of Catecholamines. The steps in the synthesis
of DA, NE (noradrenaline), and epinephrine (adrenaline)
are shown in Figure 8–5. Tyrosine is sequentially
3-hydroxylated and decarboxylated to form dopamine.
Dopamine is β-hydroxylated to yield norepinephrine,
which is N-methylated in chromaffin tissue to give epinephrine.
The enzymes involved have been identified,
HO
HO
HO
4
TYROSINE
3
H
β
C
H COOH
tyrosine-3-monooxygenase
DOPA
DOPAMINE
NOREPINEPHRINE
HO
HO
HO
HO
HO
NH 2
EPINEPHRINE
HO
H
C
H
H
C
H
H
C
H
C
α
CH
(tyrosine hydroxylase)
tetrahydrobiopterin
CH NH 2
COOH
aromatic L-amino acid
pyridoxal phosphate
CH 2
dopamine β-hydroxylase
ascorbate
CH 2
OH
phenylethanolamine-
N-methyltransferase
S-adenosylmethionine
CH 2
NH 2
decarboxylase
NH 2
OH CH 3
Figure 8–5. Steps in the enzymatic synthesis of dopamine, norepinephrine
and epinephrine. The enzymes involved are shown
in red; essential cofactors in italics. The final step occurs only in
the adrenal medulla and in a few epinephrine-containing
neuronal pathways in the brainstem.
N