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

492
SECTION II
NEUROPHARMACOLOGY
Prefrontal
cortex
(PFC)
N. Accumbens
(NAc)
PFC
NAc
VP
Glu
GABA
MOR
Hippocampus
MOR
VTA
μ opiate
DA
Amygdala
Reward
Ventral tegmental
area (VTA)
Figure 18–7. Schematic pathways underlying rewarding properties
of opiates.
Upper panel: This saggital section of rat brain displays simplified
DA and GABA inputs from the ventral tegmental area (VTA)
and prefrontal cortex (PFC), respectively, into the nucleus
accumbens (NAc).
Lower panel: Neurons are labeled with their primary neurotransmitters.
At a cellular level, MOR agonists reduce excitability and
transmitter release at the sites indicated by inhbiting Ca 2+ influx
and enhancing K + current (see Figure 18-6). Thus, opiateinduced
inhibition in the VTA on GABA-ergic interneurons or in
the NAc reduce GABA-mediated inhibition and increase outflow
from the ventral pallidum (VP), which appears to correlate with
a positive reinforcing state (enhanced reward).
inhibition of local GABAergic neuronal activity, which otherwise
acts to inhibit DA outflow (Xi and Stein, 2002).
Respiration. Although effects on respiration are readily
demonstrated, clinically significant respiratory depression
rarely occurs with standard analgesic doses in the
absence of other contributing variables (discussed in
the next sections). It should be stressed, however,
that respiratory depression represents the primary
cause of morbidity secondary to opiate therapy. In
humans, death from opiate poisoning is nearly always
due to respiratory arrest or obstruction (Pattinson,
2008). Opiates depress all phases of respiratory activity
(rate, minute volume, and tidal exchange) and produce
irregular and aperiodic breathing. The diminished
respiratory volume is due primarily to a slower rate of
breathing; with toxic amounts of opioids, the rate may fall
to 3-4 breaths per minute. The respiratory depression is
discernible even with doses too small to disturb consciousness
and increases progressively as the dose is
increased. After large doses of morphine or other agonists,
patients will breathe if instructed to do so, but
without such instruction, they may remain relatively
apneic. Thus, opioids must be used with caution in
patients with asthma, COPD, cor pulmonale, decreased
respiratory reserve, preexisting respiratory depression,
hypoxia, or hypercapnia to avoid apnea due to a
decrease in respiratory drive coinciding with an
increase airway resistance. While respiratory depression
is not considered to be a favorable therapeutic
effect of opiates, their ability to suppress respiratory
drive is used to therapeutic advantage to treat dyspnea
resulting, for example, in patients with chronic obstructive
pulmonary disease (COPD), where air hunger leads
to extreme agitation, discomfort, and gasping; similarly,
opiates find use in patients who require artificial ventilation
(Clemens and Klaschik, 2007).
Mechanisms Underlying Respiratory Depression. Respiratory rate and
tidal volume depend upon intrinsic rhythm generators located in the
ventrolateral medulla. These systems generate a “respiratory”
rhythm that is driven by afferent input reflecting the partial pressure
of arterial O 2
as measured by chemosensors in the carotid and
aortic bodies and CO 2
as measured by chemosensors in the brainstem.
Morphine-like opioids depress respiration through MOR and
DOR receptors in part by a direct depressant effect on rhythm generation,
with changes in respiratory pattern and rate observed at
lower doses than changes in tidal volume. A key property of opiate
effects on respiration is the depression of the ventilatory response
to increased CO 2
. This effect is mediated by opiate depression of the
excitability of brainstem chemosensory neurons. In addition to the
effects on the CO 2
response, opiates will depress ventilation otherwise
driven by hypoxia though an effect upon carotid and aortic
body chemosensors. Importantly, with opiates, hypoxic stimulation
of chemoreceptors still may be effective when opioids have
decreased the responsiveness to CO 2
, and inhalation of O 2
may
remove the residual drive resulting from the elevated PO 2
and produce
apnea (Pattinson, 2008). In addition to the effect upon respiratory
rhythm and chemosensitivity, opiates can have mechanical
effects on airway function by increasing chest wall rigidity and
diminishing upper airway patency (Lalley, 2008).