Page 301 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 16 Histamine, Serotonin, & the Ergot Alkaloids 287

Melatonin Pharmacology

Melatonin is N-acetyl-5-methoxytryptamine (Figure 16–2), a Other studies suggest that melatonin has antiapoptotic effects
simple methoxylated and N-acetylated product of serotonin in experimental models. Recent research implicates melatonin
found in the pineal gland. It is produced and released primarily receptors in depressive disorders. Insomnia associated with
at night and has long been suspected of playing a role in diurnal autism spectrum disorder may respond to melatonin.
cycles of animals and the sleep-wake behavior of humans. Melatonin is promoted commercially as a sleep aid by
Melatonin receptors have been characterized in the central the food supplement industry (see Chapter 64). There is an
nervous system and several peripheral tissues. In the brain, MT 1 extensive literature supporting its use in ameliorating jet lag.
and MT 2 receptors are found in membranes of neurons in the supra- It is used in oral doses of 0.5–5 mg, usually administered at the
chiasmatic nucleus of the hypothalamus, an area associated— destination bedtime. Ramelteon is a selective MT 1 and MT 2
from lesioning experiments—with circadian rhythm. MT 1 and agonist that is approved for the medical treatment of insom-
MT 2 are seven-transmembrane G i protein-coupled receptors. nia. This drug has no addiction liability (it is not a controlled
The result of receptor binding is inhibition of adenylyl cyclase. A substance), and it appears to be distinctly more efficacious
third receptor, MT 3 , is an enzyme; binding to this site has a poorly than melatonin (but less efficacious than benzodiazepines) as
defined physiologic role, possibly related to intraocular pressure. a hypnotic. It is metabolized by P450 enzymes and should not
Activation of the MT 1 receptor results in sleepiness, whereas the be used in individuals taking CYP1A2 inhibitors. It has a half-life
MT 2 receptor may be related to the light-dark synchronization of of 1–3 hours and an active metabolite with a half-life of up to
the biologic circadian clock. Melatonin has also been implicated 5 hours. Ramelteon may increase prolactin levels. Tasimelteon
in energy metabolism and obesity, and administration of the is a newer MT 1 and MT 2 agonist that is approved for non-
agent reduces body weight in certain animal models. However, 24-hour sleep-wake disorder. Agomelatine, an MT 1 and MT 2
its role in these processes is poorly understood, and there is no agonist and a 5-HT 2C antagonist, is approved in Europe for use
evidence that melatonin itself is of any value in obesity in humans. in major depressive disorder.

by chemical triggers such as cancer chemotherapy drugs. 5-HT the tumor. Serotonin may also cause hyperventilation as a result
1P
and 5-HT receptors also play important roles in enteric nervous of the chemoreceptor reflex or stimulation of bronchial sensory
4
system function. nerve endings.
Like histamine, serotonin is a potent stimulant of pain and itch
sensory nerve endings and is responsible for some of the symp- 3. Cardiovascular system—Serotonin directly causes the
toms caused by insect and plant stings. In addition, serotonin is a contraction of vascular smooth muscle, mainly through 5-HT
2
powerful activator of chemosensitive endings located in the coro- receptors. In humans, serotonin is a powerful vasoconstrictor except
nary vascular bed. Activation of 5-HT receptors on these afferent in skeletal muscle and the heart, where it dilates blood vessels.
3
vagal nerve endings is associated with the chemoreceptor reflex At least part of the 5-HT-induced vasodilation requires the
(also known as the Bezold-Jarisch reflex). The reflex response con- presence of vascular endothelial cells. When the endothelium
sists of marked bradycardia and hypotension, and its physiologic is damaged, coronary vessels are constricted by 5-HT. As noted
role is uncertain. The bradycardia is mediated by vagal outflow previously, serotonin can also elicit reflex bradycardia by activa-
to the heart and can be blocked by atropine. The hypotension is tion of 5-HT receptors on chemoreceptor nerve endings. A
3
a consequence of the decrease in cardiac output that results from triphasic blood pressure response is often seen following injec-
bradycardia. A variety of other agents can activate the chemore- tion of serotonin in experimental animals. Initially, there is a
ceptor reflex. These include nicotinic cholinoceptor agonists and decrease in heart rate, cardiac output, and blood pressure caused
some cardiac glycosides, eg, ouabain. by the chemoreceptor response. After this decrease, blood pressure
Although serotonergic neurons are not found below the increases as a result of vasoconstriction. The third phase is again
site of injury to the adult spinal cord, constitutive activity a decrease in blood pressure attributed to vasodilation in vessels
of 5-HT receptors may play a role following such a lesion— supplying skeletal muscle. In contrast, pulmonary and renal vessels
administration of 5-HT blockers appears to reduce skeletal seem very sensitive to the vasoconstrictor action of serotonin.
2
muscle spasm following this type of injury. Studies in knockout mice suggest that 5-HT, acting on
5-HT , 5-HT , and 5-HT receptors, is needed for normal
1A
2
4
2. Respiratory system—Serotonin has a small direct stimulant cardiac development in the fetus. On the other hand, chronic
effect on bronchiolar smooth muscle in normal humans, probably exposure of adults to 5-HT agonists is associated with val-
2B
receptors. It also appears to facilitate acetylcholine receptor gene are
via 5-HT 2A vulopathy and adult mice lacking the 5-HT 2B
release from bronchial vagal nerve endings. In patients with protected from cardiac hypertrophy. Preliminary studies suggest
carcinoid syndrome, episodes of bronchoconstriction occur in that 5-HT antagonists can prevent development of pulmonary
2B
response to elevated levels of the amine or peptides released from hypertension in animal models.