DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Factors Exacerbating Opiate-Induced Respiratory Depression. A number
of factors are recognized as increasing the risk of opiate-related
respiratory depression even at therapeutic doses:
• Other medications. The combination of opiates with other
depressant medications, such as general anesthetics, tranquilizers,
alcohol, or sedative-hypnotics, produces additive depression
of respiratory activity.
• Sleep. Natural sleep produces a decrease in the sensitivity of the
medullary center to CO 2
, and the depressant effects of morphine
and sleep are at least additive. Obstructive sleep apnea is considered
to be an important risk factor for increasing the likelihood
of fatal respiratory depression.
• Age. Newborns can show significant respiratory depression and
desaturation; and this may be evident in lower Apgar scores if
opioids are administered parenterally to women within 2-4 hours
of delivery because of transplacental passage of opioids. Elderly
patients are at greater risk of depression because of reduced lung
elasticity, chest wall stiffening, and decreased vital capacity.
• Disease. Opiates may cause a greater depressant action in patients
with chronic cardiopulmonary or renal diseases because they can
manifest a desensitization of their response to increased CO 2
.
• COPD. Enhanced depression can also be noted in patients with
chronic obstructive pulmonary disease (COPD) and sleep apnea
secondary to diminished hypoxic drive.
• Relief of Pain. Because pain stimulates respiration, removal of
the painful condition (as with the analgesia resulting from the
therapeutic use of the opiate) will reduce the ventilatory drive
and lead to apparent respiratory depression.
Sedation. Opiates can produce drowsiness and cognitive impairment.
Such depression can augment respiratory impairment. These effects
are most typically noted following initiation of opiate therapy or after
dose incrementation. Importantly, these effects upon arousal resolve
over a few days. As with respiratory depression, the degree of drug
effect can be enhanced by a variety of predisposing patient factors
including dementia, encephalopathies, or brain tumors as well as
other depressant medications, including sleep aids, antihistamines,
antidepressants, and anxiolytics (Cherny, 1996).
Different Opiates. Numerous studies have compared morphine and
morphine-like opioids with respect to their ratios of analgesic to
respiratory-depressant activities, and most have found that when
equianalgesic doses are used, there is no significant difference. Maximal
respiratory depression occurs within 5-10 minutes of intravenous
administration of morphine or within 30-90 minutes of intramuscular
or subcutaneous administration. Maximal respiratory depressant
effects occur more rapidly with more lipid-soluble agents. After therapeutic
doses, respiratory minute volume may be reduced for as long
as 4-5 hours. Agents that have persistent kinetics, such as methadone,
must be carefully monitored, particularly after dose incrementation.
Management of Opiate Depression. Life-threatening respiratory
depression produced by any opiate agonist can be readily reversed by
delivery of an opiate antagonist. Conversely, the ability to reverse
the somnolent patient is considered to be indicative of an opiatemediated
effect. It is important to remember that most opiate antagonists
have a relatively short duration of action as compared to an
agonist such as morphine or methadone and fatal “re-narcotization”
can occur if vigilance is not exercised.
Neuroendocrine Effects. The regulation of the release
of hormones and factors from the pituitary is under complex
regulation by opiate receptors in the hypothalamicpituitary-adrenal
(HPA) axis. Broadly considered,
morphine-like opioids block the release of a large number
of HPA hormones.
Sex Hormones. In males, acute opiate therapy reduces plasma cortisol,
testosterone, and gonadotrophins. Inhibition of adrenal function
is reflected by reduced cortisol production and reduced adrenal
androgens (dehydroepiandrosterone, DHEA). In females, morphine
will additionally result in lower LH and FSH release. In both males
and females, chronic therapy can result in endocrinopathies, including
hypogonadotrophic hypogonadism. In men, this may result in
decreased libido and, with extended exposure, reduced secondary
sex characteristics. In women these exposures are associated with
menstrual cycle irregularities. Importantly, these changes are
reversible with removal of the opiate.
The mechanisms of the opiate regulation of gonadotrophin
release may reflect a direct effect upon secreting pituicytes and an
indirect action, through an effect on receptors present on hypothalamic
neurons, to block release of gonadotropin-releasing hormone
(GnRH) and corticotropin-releasing hormone (CRH). This reduction
of the releasing factors leads to reduced release of luteinizing
hormone (LH), follicle-stimulating hormone (FSH), ACTH, and
β-endorphin. This series of events leads to reduced circulating testosterone
and cortisol. Secretion of thyrotropin is relatively unaffected.
Prolactin. Prolactin release from lactotrope cells in the anterior pituitary
is under inhibitory control by dopamine released from tuberoinfundibulum
neurons of the arcuate nucleus. MOR agonists act
presynaptically on these dopamine-releasing terminals to inhibit DA
release and thereby increase plasma prolactin.
Growth Hormone. Growth hormone (GH) is released in a pulsatile
fashion from somatotrophs in the anterior pituitary. GH-releasing
hormone (GHRH) neurons in the hypothalamic arcuate nucleus and
inhibitory input from somatostatin (SST) cells in the periventricular
nucleus regulate this. Although some opioids increase GH release,
possibly by inhibiting SST release, acute morphine has little effect
on plasma GH concentration (Bluet-Pajot et al., 2001).
Antidiuretic Hormone and Oxytocin. The effects of opiates on ADH
and oxytocin release are complex. These hormones are synthesized
in the perikarya of the magnocellular neurons in the parventricular
and supraoptic nuclei of the hypothalamus and released from the
posterior pituitary (Chapter 38). ADH (vasopressin) release can
occur secondary to surgical stress, hypovolemia, hypotension, and
low osmolarity, while oxytocin release typically is released with
afferent stimuli related to the milk ejection pathway. KOR agonists
inhibit the release of oxytocin and antidiuretic hormone (and cause
prominent diuresis). In humans, the administration of MOR agonists
has little effect or tends to produce antidiuretic effects. Morphine
reduces oxytocin secretion in nursing women (Lindow et al., 1999).
It should be noted that agents such as morphine may yield a hypotension
secondary to histamine release and this would, by itself, promote
ADH release. Based on electrophysiology and localization of
opiate receptors, these effects upon vasopressin and oxytocin release
may reflect both a direct effect upon terminal secretion as well as
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CHAPTER 18
OPIOIDS, ANALGESIA, AND PAIN MANAGEMENT