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

200 by activation of β 2
adrenergic receptors, angiotensin
AT 2
receptors, and nACh receptors. All of these receptors
can be targets for agonists and antagonists (Kubista
and Boehm, 2006).
Termination of the Actions of Catecholamines. The
actions of NE and epinephrine are terminated by:
SECTION II
NEUROPHARMACOLOGY
• reuptake into nerve terminals by NET
• dilution by diffusion out of the junctional cleft and
uptake at extraneuronal sites by ENT, OCT 1, and
OCT 2
Following uptake, catecholamines can be metabolized
(in neuronal and non-neuronal cells) or re-stored
in vesicles (in neurons). Two enzymes are important
in the initial steps of metabolic transformation of
catecholamines—monoamine oxidase (MAO) and
catechol-O-methyltransferase (COMT). In addition,
catecholamines are metabolized by sulfotransferases
(Dooley, 1998) (Chapter 6). However, termination of
action by a powerful degradative enzymatic pathway,
such as that provided by AChE at sites of cholinergic
transmission, is absent from the adrenergic nervous system.
The importance of neuronal reuptake of catecholamines
is shown by observations that inhibitors of
this process (e.g., cocaine and imipramine) potentiate
the effects of the neurotransmitter; inhibitors of MAO
and COMT have relatively little effect. However, MAO
metabolizes transmitter that is released within the nerve
terminal. COMT, particularly in the liver, plays a major
role in the metabolism of endogenous circulating and
administered catecholamines.
Both MAO and COMT are distributed widely throughout the
body, including the brain; the highest concentrations of each are in the
liver and the kidney. However, little or no COMT is found in sympathetic
neurons. In the brain, there is also no significant COMT in presynaptic
terminals, but it is found in some postsynaptic neurons and glial
cells. In the kidney, COMT is localized in proximal tubular epithelial
cells, where DA is synthesized, and is thought to exert local diuretic
and natriuretic effects. The physiological substrates for COMT include
L-dopa, all three endogenous catecholamines (DA, NE, and epinephrine),
their hydroxylated metabolites, catecholestrogens, ascorbic acid,
and dihydroxyindolic intermediates of melanin (Männistö and
Kaakkola, 1999). There are distinct differences in the cytological locations
of the two enzymes; MAO is associated chiefly with the outer
surface of mitochondria, including those within the terminals of sympathetic
or central noradrenergic neuronal fibers, whereas COMT is
largely cytoplasmic except in the chromaffin cells of the adrenal
medulla, where COMT is present as a membrane-bound form. These
factors are of importance both in determining the primary metabolic
pathways followed by catecholamines in various circumstances and
in explaining the effects of certain drugs. Two different isozymes of
MAO (MAO-A and MAO-B) are found in widely varying proportions
in different cells in the CNS and in peripheral tissues. In the periphery,
MAO-A is located in the syncytiotrophoblast layer of term placenta
and liver, whereas MAO-B is located in platelets, lymphocytes,
and liver. In the brain, MAO-A is located in all regions containing catecholamines,
with the highest abundance in the locus ceruleus. MAO-B,
on the other hand, is found primarily in regions that are known to synthesize
and store 5-HT. MAO-B is most prominent in the nucleus
raphe dorsalis but also in the posterior hypothalamus and in glial cells
in regions known to contain nerve terminals. MAO-B is also present
in osteocytes around blood vessels (Abell and Kwan, 2001). Selective
inhibitors of these two isozymes are available (Chapter 15).
Irreversible antagonists of MAO-A (e.g., phenelzine, tranylcypromine,
and isocarboxazid) enhance the bioavailability of tyramine contained
in many foods; tyramine-induced NE release from sympathetic neurons
may lead to markedly increased blood pressure (hypertensive crisis).
Selective MAO-B inhibitors (e.g., selegiline) or reversible
MAO-A–selective inhibitors (e.g., moclobemide) are less likely to
cause this potential interaction (Volz and Geiter, 1998; Wouters, 1998).
MAO inhibitors are useful in the treatment of Parkinson’s disease and
mental depression (Chapters 15 and 22).
Inhibitors of MAO (e.g., pargyline and nialamide) can cause
an increase in the concentration of NE, DA, and 5-HT in the brain
and other tissues accompanied by a variety of pharmacological
effects. No striking pharmacological action in the periphery can be
attributed to the inhibition of COMT. However, the COMT inhibitors
entacapone and tocapone have been found to be efficacious in the
therapy of Parkinson’s disease (Chong and Mersfelder, 2000)
(Chapter 22).
There is ongoing passive leakage of catecholamines from
vesicular storage granules of sympathetric neurons and adrenal
medullary chromaffin cells. As a consequence, most metabolism of
catecholamines takes place in the same cells where the amines are
synthesized and stored. VMAT2 effectively sequesters ~90% of the
amines leaking into the cytoplasm back into storage vesicles; ~10%
escapes sequestration and is metabolized (Eisenhofer et al., 2004).
Sympathetic nerves contain MAO but not COMT, and this
MAO catalyzes only the first step of a two-step reaction. MAO converts
NE or epinephrine into a short-lived intermediate, DOPGAL,
which undergoes further metabolism in a second step catalyzed by
another group of enzymes forming more stable alcohol- or acid-deaminated
metabolites. Aldehyde dehydrogenase metabolizes DOPGAL to
3,4-dihydroxymandelic acid (DOMA), while aldehyde reductase
metabolized DOPGAL to 3,4-dihydroxyphenyl glycol (DOPEG). In
addition to aldehyde reductase, a related enzyme, aldose reductase,
can also reduce a catecholamine to its corresponding alcohol. This latter
enzyme is present in sympathetic neurons and adrenal chromaffin
cells. Under normal circumstances, DOMA is an insignificant metabolite
of NE and epinephrine, with DOPEG being the main metabolite
produced by deamination in sympathetic neurons and adrenal
medullary chromaffin cells.
Once it leaves the sites of formation (sympathetic neurons,
adrenal medulla), DOPEG is converted to 3-methyl, 4-hydroxy
phenylglycol (MOPEG) by COMT. Therefore most MOPEG comes
from the extraneuronal O-methylation of DOPEG produced in and
diffusing rapidly from sympathetic neurons into the extracellular
fluid. MOPEG is then converted to vanillylmandelic acid (VMA) by
the sequential action of alcohol and aldehyde dehydrogenase.
MOPEG is first converted to the unstable aldehyde metabolite