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PART II Pharmacology of Specific Drug Groups

tionate increase in mistakes. The need for sleep can be delayed
with amphetamine but not diminished. Drugs related to
amphetamine include dextroamphetamine and methamphet-
amine. Compared with amphetamine, both tend to have more
effects on the CNS relative to the periphery. The addition of
a single hydroxyl group (4-OH) to yield hydroxyamphet-
amine produces a drug with less CNS activity.
Acute tolerance (tachyphylaxis) is a common outcome of
repeated administration of indirect-acting adrenergic drugs.
Multiple doses of either mixed-acting or indirect-acting adren-
ergic agonists may lead to a depletion of the neurotransmitter,
resulting in a reduction or loss of activity in response to nerve
stimulation. These drugs are also susceptible as a class to
several drug interactions. Compounds such as the tricyclic
antidepressants and some adrenergic neuron-blocking drugs
interfere competitively with the uptake of indirect-acting ago-
nists into adrenergic nerve terminals and block their subse-
quent release of norepinephrine. MAO inhibitors promote the
accumulation of intraneuronal catecholamines, which are
released by these agonists. The combination of an MAO
inhibitor and an indirect-acting or mixed-acting sympathomi-
metic drug typically results in excessive release of catechol-
amines with serious consequences. Some indirect-acting
compounds, such as tyramine, occur naturally in several foods
and beverages, and pose a great risk to patients taking MAO
inhibitors.
ABSORPTION, FATE, AND EXCRETION
As noted in the section on chemistry and structure-activity
relationships, the route for administering adrenergic agonists
is determined by the chemical structure. All catecholamines
and certain other drugs, unless specifically modified at the α
carbon of the side chain, are subject to enzymatic destruction
in the gastrointestinal tract. Catecholamines are usually
administered systemically by parenteral injection or intrave-
nous infusion. Topical instillation and inhalation are the pre-
ferred routes of administration for ocular and respiratory
applications, respectively.
The inactivation and metabolic disposal of catecholamines
can involve many processes, as illustrated by the fate of
endogenously released norepinephrine (Figure 6-4). After
neuronal release, a large portion (80% in some cases) of the
adrenergic neurotransmitter is returned to the nerve terminal
by an active neuronal uptake process. What remains in the
junctional cleft is subjected to O-methylation by catechol-O-
methyltransferase (COMT) after uptake by postjunctional
effector cells. Norepinephrine that diffuses out of the junction
may be taken up by other cells and metabolized by COMT.
When the transmitter is O-methylated to normetanephrine,
it can no longer be transported into the adrenergic nerve
terminal but is instead carried by the blood to the liver, where
it is largely deaminated by hepatic MAO.12 Some portion of
the released neurotransmitter also diffuses away from the
junctional cleft to enter the circulation intact.
Of the norepinephrine that is actively transported back
into the neuron, a large part is actively returned to the storage
vesicles from which it can be released again on neuronal
stimulation. A smaller portion is deaminated by MAO located
in the outer membrane of the mitochondria to form 3,4-
dihydroxyphenylglycoaldehyde. Most of the aldehyde is con-
verted to a glycol, the remainder to an acid. Both metabolites
enter the circulation and are eventually O-methylated by
COMT. The major metabolic products of norepinephrine
resulting from the combined action of MAO and COMT
(and several supportive reductases and dehydrogenases) are
3-methoxy-4-hydroxymandelic acid, also referred to as vanil-
lylmandelic acid, and 3-methoxy-4-hydroxyphenylglycol.10
About 90% of the total endogenous norepinephrine load
excreted in the urine is in the form of vanillylmandelic acid
and 3-methoxy-4-hydroxyphenylglycol, with the remainder
consisting of other O-methylated compounds and lesser quan-
tities of other derivatives and unmetabolized norepineph-
rine.28 Several of these products are conjugated to the sulfate
or glucuronide before being excreted by the kidney.
Exogenously administered catecholamines and endoge-
nous dopamine and epinephrine are transported and
metabolized in much the same manner as norepinephrine.
Nevertheless, there are some differences. The metabolic inac-
tivation of epinephrine and most injected catecholamines
(including norepinephrine) largely depends on COMT
because COMT is widely distributed throughout the body
and the administration of exogenous catecholamines allows
them to be distributed far beyond the adrenergic neuroeffec-
tor junctions. The relative shift toward COMT for the initial

Адренергический Extraneural tissues Urine

Synaptic
нейрон cleft Hepatic
and
renal
conjugation
MAO КОМТ VMA, MHPG
MAO
НА КОМТ Normetanephrine

NE
Везикула
Epinephrine
Exogenous
catecholamines
FIGURE 6-4  Biotransformation and excretion of catecholamines. After release, up to 80% of norepi-
nephrine (NE) is taken up by a reuptake process into the nerve terminal, where most is recycled into
storage vesicles, and some is metabolized by mitochondrial monoamine oxidase (MAO). Extraneuronal
tissues metabolize endogenously released catecholamines through catechol-O-methyl transferase
(COMT) and MAO. Excreted substances include the metabolites 3-methoxy-4-hydroxymandelic acid
(VMA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), and normetanephrine, small amounts of unme-
tabolized catecholamines, and related sulfate and glucuronide conjugates. Injected vasoconstrictors and
some other adrenergic agonists are also biotransformed and excreted by some of these same pathways.