Page 299 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 16 Histamine, Serotonin, & the Ergot Alkaloids 285

first discovered. Although these agents are not the most efficacious
available, their ability to reduce gastric acid secretion with very low CH 2 NH 3 +
toxicity has made them extremely popular as over-the-counter prep- CH COO –
arations. These drugs are discussed in more detail in Chapter 62.
N
H
H - & H -RECEPTOR ANTAGONISTS L-tryptophan
4
3
Although no selective H or H ligands are presently available
3
4
for general clinical use, there is great interest in their therapeutic
potential. H -selective ligands may be of value in sleep disorders,
3
narcolepsy, obesity, and cognitive and psychiatric disorders. HO CH 2 CH NH 2
Tiprolisant, an inverse H -receptor agonist, has been shown to 2
3
reduce sleep cycles in mutant mice and in humans with narco- N
lepsy. Increased obesity has been demonstrated in both H - and H
1
H -receptor knockout mice; however, H inverse agonists decrease 5-Hydroxytryptamine (serotonin)
3
3
feeding in obese mouse models. As noted in Chapter 29, several
atypical antipsychotic drugs have significant affinity for H receptors
3
(and cause weight gain).
Because of the homology between the H and H receptors, H
4
3
some H ligands also have affinity for the H receptor. H blockers O CH 2 N CH 3
4
3
4
have potential in chronic inflammatory conditions such as H C CH 2 C
3
asthma, in which eosinophils and mast cells play a prominent role. O
No selective H ligand is available for use in humans, but in addi- N
4
H
tion to research agents listed in Table 16–1, many H -selective
1
Melatonin
blockers (eg, diphenhydramine, cetirizine, loratadine) show some (N-acetyl-5-methoxytryptamine)
affinity for this receptor. Several studies have suggested that
H -receptor antagonists may be useful in pruritus, asthma, allergic
4
rhinitis, and pain conditions. FIGURE 16–2 Synthesis of serotonin and melatonin from
l-tryptophan.
■ SEROTONIN by hydroxylation of the indole ring followed by decarboxylation
(5-HYDROXYTRYPTAMINE) of the amino acid (Figure 16–2). Hydroxylation at C5 by
tryptophan hydroxylase-1 is the rate-limiting step and can be
Before the identification of 5-hydroxytryptamine (5-HT), it was blocked by p-chlorophenylalanine (PCPA; fenclonine) and by
known that when blood is allowed to clot, a vasoconstrictor (tonic) p-chloroamphetamine. These agents have been used experimen-
substance is released from the clot into the serum. This substance tally to reduce serotonin synthesis in carcinoid syndrome but are
was called serotonin. Independent studies established the existence too toxic for general clinical use. Telotristat ethyl, an orally active
of a smooth muscle stimulant in intestinal mucosa. This was hydroxylase inhibitor, has been approved for the treatment of
called enteramine. The synthesis of 5-hydroxytryptamine in 1951 diarrhea due to carcinoid tumor.
led to the identification of serotonin and enteramine as the same After synthesis, the free amine is stored in vesicles or is rapidly
metabolite of 5-hydroxytryptophan. inactivated, usually by oxidation by monoamine oxidase (MAO).
Serotonin is an important neurotransmitter, a local hormone In the pineal gland, serotonin serves as a precursor of melatonin, a
in the gut, a component of the platelet clotting process, and is melanocyte-stimulating hormone that has complex effects in several
thought to play a role in migraine headache and several other clini- tissues. In mammals (including humans), over 90% of the serotonin
cal conditions, including carcinoid syndrome. This syndrome is an in the body is found in enterochromaffin cells in the gastrointestinal
unusual manifestation of carcinoid tumor, a neoplasm of entero- tract. In the blood, serotonin is found in platelets, which are able to
chromaffin cells. In patients whose tumor is not surgically resect- concentrate the amine by means of an active serotonin transporter
able, a serotonin antagonist may constitute a useful treatment. mechanism (SERT) similar to that in the membrane of serotonergic
nerve endings. Once transported into the platelet or nerve ending,
BASIC PHARMACOLOGY OF SEROTONIN 5-HT is concentrated in vesicles by a vesicle-associated transporter
(VAT) that is blocked by reserpine. Serotonin is also found in the
Chemistry & Pharmacokinetics raphe nuclei of the brainstem, which contain cell bodies of sero-
tonergic neurons that synthesize, store, and release serotonin as a
Like histamine, serotonin is widely distributed in nature, being transmitter. Stored serotonin can be depleted by reserpine in much
found in plant and animal tissues, venoms, and stings. It is syn- the same manner as this drug depletes catecholamines from vesicles
thesized in biologic systems from the amino acid l-tryptophan in adrenergic nerves and the adrenal medulla (see Chapter 6).