Page 1157 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 64 Dietary Supplements & Herbal Medications 1143

Drug Interactions & Precautions sleep-phase syndrome. It has been reported to improve sleep onset,
duration, and quality when administered to healthy volunteers,
Glucosamine sulfate may increase the international normalized suggesting a pharmacologic hypnotic effect. Melatonin has also
ratio (INR) in patients taking warfarin, increasing the risk for been shown to increase rapid eye movement (REM) sleep. These
bruising and bleeding. The mechanism is not well understood observations have been applied to the development of ramelteon,
and may be dose-related as increases in INR have occurred when a prescription hypnotic that is an agonist at melatonin receptors
the glucosamine dose was increased. Until more is known, the (see Chapter 22).
combination should be avoided or very carefully monitored.
Clinical studies in patients with primary insomnia have shown
that oral melatonin supplementation may alter sleep architecture.
Dosage Melatonin appears effective in some patients who develop insom-
The oral dosage used most often in clinical trials is 500 mg three nia from β blockers. Subjective and objective improvements in
times daily or 1500 mg once daily. Glucosamine does not have sleep quality and improvements in sleep onset and sleep duration
direct analgesic effects, and improvements in function, if any, may have been reported. Specifically, melatonin taken at the desired
not be observed for 1–2 months. bedtime, with bedroom lights off, has been shown to improve
morning alertness and quality of sleep as compared with placebo.
MELATONIN These effects have been observed in both young and older adults
(18–80 years of age). Interestingly, baseline endogenous melatonin
levels were not predictive of exogenous melatonin efficacy.
Melatonin, a serotonin derivative produced by the pineal gland
and some other tissues (see also Chapter 16), is believed to be 3. Pre- and postoperative anxiety in adults—Melatonin given
responsible for regulating sleep-wake cycles. Release coincides as a premedication has been shown to reduce preoperative anxiety
with darkness; it typically begins around 9 pm and lasts until about in adults. Melatonin may be as effective as midazolam in reducing
4 am. Melatonin release is suppressed by daylight. Melatonin has anxiety before a surgical procedure (measured 50–100 minutes after
also been studied for a number of other functions, including con- administration). The effect of melatonin on postoperative anxiety in
traception, protection against endogenous oxidants, prevention adults is mixed, but studies support an overall reduction in anxiety
of aging, treatment of depression, HIV infection, and a variety of as compared to preoperative anxiety levels.
cancers. Currently, melatonin is most often used to prevent jet lag
and to induce sleep. 4. Female reproductive function—The presence of melato-
nin within the female reproductive system appears widespread in
Pharmacologic Effects & Clinical Uses mammals, and research suggests it plays a role in reducing oxida-
tive stress. Melatonin receptors have been identified in ovarian
1. Jet lag—Jet lag, a disturbance of the sleep-wake cycle, occurs granulosa cell membranes, and significant amounts of melatonin
when there is a disparity between the external time, ie, hours of have been detected in follicular fluid. Some studies suggest it
daylight or darkness, and the traveler’s endogenous circadian clock can be used as an adjunctive therapy in the treatment of infertil-
(internal time). The internal time regulates not only daily sleep ity during in vitro fertilization by reducing oxidative stress and
rhythms but also body temperature and many metabolic systems. thereby improving the quality of oocytes and embryos during
The synchronization of the circadian clock relies on light as the ovulation induction and egg retrieval. Melatonin requirements
most potent “zeitgeber” (time giver). increase during pregnancy, and researchers are evaluating the role
Jet lag is especially common among frequent travelers and air-
plane cabin crews. Typical symptoms of jet lag may include daytime of melatonin in preeclampsia and neonatal neurologic morbidity.
Importantly, melatonin has been shown to lack teratogenic effects
drowsiness, insomnia, frequent awakenings, and gastrointestinal when taken during pregnancy. Melatonin supplementation may
upset. Clinical studies of melatonin have reported subjective reduc- decrease prolactin release in women and therefore should be used
tion in daytime fatigue, improved mood, and a quicker recovery cautiously or not at all while nursing.
time (return to normal sleep patterns, energy, and alertness). These
outcomes are also supported by a systematic review that showed 5. Male reproductive function—Melatonin receptors have
melatonin was better than placebo in helping patients fall asleep been identified on spermatozoa, suggesting melatonin may play
faster and to sleep better at their destination. When traveling across a role in sperm function. When melatonin was added to semen
five or more time zones, jet lag symptoms are reduced when taking samples, sperm motility was increased and early apoptosis was
melatonin close to the target bedtime (10 pm to midnight) at the inhibited. These findings suggest that melatonin may be impor-
new destination. The benefit of melatonin is thought to be greater tant in male fertility; however, more research is needed.
as more time zones are crossed. In addition, melatonin appears
more effective for eastbound travel than for westward travel. Finally, Adverse Effects
maximizing exposure to daylight on arrival at the new destination
can also aid in resetting the internal clock. Melatonin appears to be well tolerated and is often used in prefer-
ence to over-the-counter “sleep-aid” drugs. Although melatonin is
2. Insomnia—Melatonin has been studied in the treatment associated with few adverse effects, some next-day drowsiness has
of various sleep disorders, including insomnia and delayed been reported as well as fatigue, dizziness, headache, and irritability.