Biogenic Amines

Biogenic Amines — Actions and
Pharmacological Implications
Dopamine A. As the precursor of norepinephrine
and epinephrine,
dopamine is found in sympathetic (adrenergic)
neurons and adrenomedullary
cells. In the CNS, dopamine itself serves
as a neuromediator and is implicated in
neostriatal motor programming,
the elicitation of emesis at the level of
the area postrema, and inhibition
of prolactin release from the anterior
pituitary.
Dopamine receptors are coupled to Gproteins
and exist as different subtypes.
D1-receptors (comprising subtypes D1
and D5) and D2-receptors (comprising
subtypes D2, D3, and D4). The aforementioned
actions are mediated mainly by
D2 receptors. When given by infusion,
dopamine causes dilation of renal and
splanchnic arteries. This effect is mediated
by D1 receptors and is utilized in the
treatment of cardiovascular shock and
hypertensive emergencies by infusion of
dopamine and fenoldopam, respectively.
At higher doses, !1-adrenoceptors
and, finally, "-receptors are activated, as
evidenced by cardiac stimulation and
vasoconstriction, respectively.
Dopamine is not to be confused with dobutamine
which stimulates "- and !-adrenoceptors
but not dopamine receptors.
Dopamine-mimetics. Administration
of the precursor L-dopa promotes
endogenous synthesis of dopamine (indication:
parkinsonian syndrome.
The ergolides, bromocriptine,
pergolide, and lisuride, are ligands at Dreceptors
whose therapeutic effects are
probably due to stimulation of D2 receptors
(indications: parkinsonism, suppression
of lactation, infertility, acromegaly.
Typical adverse effects of
these substances are nausea and vomiting.
As indirect dopamine-mimetics, (+)-
amphetamine and ritaline augment dopamine
release.
Inhibition of the enzymes involved
in dopamine degradation, catecholamine-
oxygen-methyl-transferase
(COMT) and monoamineoxidase (MAO),
is another means to increase actual
available dopamine concentration
(COMT-inhibitors, p. 188), MAOB-inhibitors.
Dopamine antagonist activity is the
hallmark of classical neuroleptics. The
antihypertensive agents, reserpine (obsolete)
and "-methyldopa, deplete neuronal
stores of the amine. A common adverse
effect of dopamine antagonists or
depletors is parkinsonism.
Histamine (B). Histamine is stored
in basophils and tissue mast cells. It
plays a role in inflammatory and allergic
reactions and produces
bronchoconstriction, increased intestinal
peristalsis, and dilation and increased
permeability of small blood vessels.
In the gastric mucosa, it is released
from enterochromaffin-like cells and
stimulates acid secretion by the parietal
cells. In the CNS, it acts as a neuromodulator.
Two receptor subtypes (G-protein-
coupled), H1 and H2, are of therapeutic
importance; both mediate vascular
responses. Prejunctional H3 receptors
exist in brain and the periphery.
Antagonists. Most of the so-called
H1-antihistamines also block other receptors,
including M-cholinoceptors and
D-receptors. H1-antihistamines are used
for the symptomatic relief of allergies
(e.g., bamipine, chlorpheniramine, clemastine,
dimethindene, mebhydroline
pheniramine); as antiemetics (meclizine,
dimenhydrinate, as overthe-
counter hypnotics (e.g., diphenhydramine).
Promethazine represents
the transition to the neuroleptic
phenothiazines. Unwanted effects
of most H1-antihistamines are lassitude
(impaired driving skills) and atropine-
like reactions (e.g., dry mouth, constipation).
At the usual therapeutic doses,
astemizole, cetrizine, fexofenadine,
and loratidine are practically devoid of
sedative and anticholinergic effects. H2-
antihistamines (cimetidine, ranitidine,
famotidine, nizatidine) inhibit gastric
acid secretion, and thus are useful in the
treatment of peptic ulcers.


Inhibitors of histamine release: One
of the effects of the so-called mast cell
stabilizers cromoglycate (cromolyn)
and nedocromil is to decrease the release
of histamine from mast cells.
Both agents are applied topically.
Release of mast cell mediators can
also be inhibited by some H1 antihistamines,
e.g., oxatomide and ketotifen,
which are used systemically.
Serotonin
Occurrence. Serotonin (5-hydroxytryptamine,
5-HT) is synthesized from Ltryptophan
in enterochromaffin cells of
the intestinal mucosa. 5-HT-synthesizing
neurons occur in the enteric nerve
plexus and the CNS, where the amine
fulfills a neuromediator function. Blood
platelets are unable to synthesize 5HT,
but are capable of taking up, storing,
and releasing it.
Serotonin receptors. Based on biochemical
and pharmacological criteria,
seven receptor classes can be distinguished.
Of major pharmacotherapeutic
importance are those designated 5-HT1,
5-HT2, 5-HT4, and 5-HT7, all of which are
G-protein-coupled, whereas the 5-HT3
subtype represents a ligand-gated nonselective
cation channel.
Serotonin actions. The cardiovascular
effects of 5-HT are complex, because
multiple, in part opposing, effects are
exerted via the different receptor subtypes.
Thus, 5-HT2A and 5-HT7 receptors
on vascular smooth muscle cells mediate
direct vasoconstriction and vasodilation,
respectively. Vasodilation and
lowering of blood pressure can also occur
by several indirect mechanisms: 5-
HT1A receptors mediate sympathoinhibition
(! decrease in neurogenic vasoconstrictor
tonus) both centrally and
peripherally; 5-HT2B receptors on vascular
endothelium promote release of
vasorelaxant mediators (NO, p. 120;
prostacyclin) 5-HT released from
platelets plays a role in thrombogenesis,
hemostasis, and the pathogenesis of
preeclamptic hypertension.
Ketanserin is an antagonist at 5-
HT2A receptors and produces antihypertensive
effects, as well as inhibition of
thrombocyte aggregation. Whether 5-
HT antagonism accounts for its antihypertensive
effect remains questionable,
because ketanserin also blocks !-adrenoceptors.
Sumatriptan and other triptans are
antimigraine drugs that possess agonist
activity at 5-HT1 receptors of the B, D
and F subtypes and may thereby alleviate
this type of headache.
Gastrointestinal tract. Serotonin
released from myenteric neurons or enterochromaffin
cells acts on 5-HT3 and
5-HT4 receptors to enhance bowel motility
and enteral fluid secretion. Cisapride
is a prokinetic agent that promotes
propulsive motor activity in the
stomach and in small and large intestines.
It is used in motility disorders. Its
mechanism of action is unclear, but
stimulation of 5HT4 receptors may be
important.
Central Nervous System. Serotoninergic
neurons play a part in various
brain functions, as evidenced by the effects
of drugs likely to interfere with serotonin.
Fluoxetine is an antidepressant
that, by blocking re-uptake, inhibits inactivation
of released serotonin. Its activity
spectrum includes significant psychomotor
stimulation, depression of appetite,
and anxiolysis. Buspirone also has
anxiolytic properties thought to be mediated
by central presynaptic 5-HT1A receptors.
Ondansetron, an antagonist at
the 5-HT3 receptor, possesses striking
effectiveness against cytotoxic drug-induced
emesis, evident both at the start
of and during cytostatic therapy. Tropisetron
and granisetron produce analogous
effects.
Psychedelics (LSD) and other psychotomimetics
such as mescaline and
psilocybin can induce states of altered
awareness, or induce hallucinations and
anxiety, probably mediated by 5-HT2A
receptors. Overactivity of these receptors
may also play a role in the genesis
of negative symptoms in schizophrenia
and sleep disturbances.