Page 300 - Basic _ Clinical Pharmacology ( PDFDrive )

286 SECTION IV Drugs with Important Actions on Smooth Muscle

Brain serotonergic neurons are involved in numerous diffuse Pharmacodynamics
functions such as mood, sleep, appetite, and temperature regula-
tion, as well as the perception of pain, the regulation of blood A. Mechanisms of Action
pressure, and vomiting (see Chapter 21). Serotonin is clearly Serotonin exerts many actions and, like histamine, displays
involved in psychiatric depression (see Chapter 30) and also many species differences, making generalizations difficult. The
appears to be involved in conditions such as anxiety and migraine. actions of serotonin are mediated through a remarkably large
Serotonergic neurons are found in the enteric nervous system of number of cell membrane receptors. The serotonin receptors
the gastrointestinal tract and around blood vessels. In rodents (but that have been characterized thus far are listed in Table 16–3.
not in humans), serotonin is also found in mast cells. Seven families of 5-HT-receptor subtypes (those given numeric
The function of serotonin in enterochromaffin cells is not fully subscripts 1 through 7) have been identified, six involving G
understood. These cells synthesize serotonin, store the amine in a protein-coupled receptors of the usual seven-transmembrane
complex with adenosine triphosphate (ATP) and other substances serpentine type and one a ligand-gated ion channel. The latter
+
+
in granules, and release serotonin in response to mechanical and (5-HT ) receptor is a member of the nicotinic family of Na /K
3
neuronal stimuli. This serotonin interacts in a paracrine fashion channel proteins.
with several different 5-HT receptors in the gut (see Chapter 62).
Some of the released serotonin diffuses into blood vessels and is B. Tissue and Organ System Effects
taken up and stored in platelets. 1. Nervous system—Serotonin is present in a variety of sites
Serotonin is metabolized by MAO, and the intermediate in the brain. Its role as a neurotransmitter and its relation to the
product, 5-hydroxyindoleacetaldehyde, is further oxidized by actions of drugs acting in the central nervous system are discussed
aldehyde dehydrogenase to 5-hydroxyindoleacetic acid (5-HIAA). in Chapters 21 and 30. Serotonin is also a precursor of melatonin in
In humans consuming a normal diet, the excretion of 5-HIAA is the pineal gland (Figure 16–2; see Box: Melatonin Pharmacology).
a measure of serotonin synthesis. Therefore, the 24-hour excre- Repinotan, a 5-HT agonist currently in clinical trials, appears to
1A
tion of 5-HIAA can be used as a diagnostic test for tumors that have some antinociceptive action at higher doses while reversing
synthesize excessive quantities of serotonin, especially carcinoid opioid-induced respiratory depression.
tumor. A few foods (eg, bananas) contain large amounts of 5-HT receptors in the gastrointestinal tract and in the vomit-
3
serotonin or its precursors and must be prohibited during such ing center of the medulla participate in the vomiting reflex (see
diagnostic tests. Chapter 62). They are particularly important in vomiting caused

TABLE 16–3 Serotonin receptor subtypes currently recognized. (See also Chapter 21.)

Receptor Postreceptor Partially Selective
Subtype Distribution Mechanism Partially Selective Agonists Antagonists
1
Raphe nuclei, hippocampus G i, ↓ cAMP 8-OH-DPAT, repinotan WAY1006351
5-HT 1A
5-HT 1B Substantia nigra, globus G i, ↓ cAMP Sumatriptan, L694247 1
pallidus, basal ganglia
Brain G i, ↓ cAMP Sumatriptan, eletriptan
5-HT 1D
Cortex, putamen G i, ↓ cAMP
5-HT 1E
Cortex, hippocampus G i, ↓ cAMP LY3344864 1
5-HT 1F
5-HT 1P Enteric nervous system G o, slow EPSP 5-Hydroxyindalpine Renzapride
5-HT 2A Platelets, smooth muscle, G q, ↑ IP 3 α-Methyl-5-HT, DOI 1 Ketanserin
cerebral cortex
Stomach fundus α-Methyl-5-HT, DOI 1 RS127445 1
5-HT 2B G q, ↑ IP 3
1
Choroid, hippocampus, α-Methyl-5-HT, DOI, lorcaserin Mesulergine
5-HT 2C G q, ↑ IP 3
substantia nigra
+
5-HT 3 Area postrema, sensory and Receptor is an Na / 2-Methyl-5-HT, m-chlorophenylbiguanide Granisetron,
+
enteric nerves K ion channel ondansetron,
others
1
5-HT 4 CNS and myenteric neurons, G s, ↑ cAMP BIMU8, renzapride, metoclopramide GR113808 1
smooth muscle
Brain ↓ cAMP
5-HT 5A,B
5-HT 6,7 Brain G s, ↑ cAMP Clozapine (5-HT 7 )
1
Research agents; for chemical names see Alexander SPH, Mathie A, Peters JA: Guide to receptors and channels (GRAC). Br J Pharmacol 2011;164 (Suppl 1):S16–17, 116–117.
cAMP, cyclic adenosine monophosphate; EPSP, excitatory postsynaptic potential; IP 3 , inositol trisphosphate.