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

554 effects on different organ systems (Nunn, 2005b).
Responses of individual organ systems to hypoxia are
summarized next.
SECTION II
NEUROPHARMACOLOGY
Respiratory System. Hypoxia stimulates the carotid and aortic
baroreceptors to cause increases in both the rate and depth of ventilation.
Minute volume almost doubles when normal individuals
inspire gas with a PO 2
of 6.6 kPa (50 mm Hg). Dyspnea is not always
experienced with simple hypoxia but occurs when the respiratory
minute volume approaches half the maximal breathing capacity; this
may occur with minimum exertion in patients in whom maximal
breathing capacity is reduced by lung disease. In general, little warning
precedes the loss of consciousness resulting from hypoxia.
Cardiovascular System. Hypoxia causes reflex activation of the sympathetic
nervous system by both autonomic and humoral mechanisms,
resulting in tachycardia and increased cardiac output. Peripheral vascular
resistance, however, decreases primarily through local autoregulatory
mechanisms, with the net result that blood pressure generally
is maintained unless hypoxia is prolonged or severe. In contrast to the
systemic circulation, hypoxia causes pulmonary vasoconstriction and
hypertension, an extension of the normal regional vascular response
that matches perfusion with ventilation to optimize gas exchange in the
lung (hypoxic pulmonary vasoconstriction).
CNS. The CNS is least able to tolerate hypoxia. Hypoxia is manifest
initially by decreased intellectual capacity and impaired judgment
and psychomotor ability. This state progresses to confusion and restlessness
and ultimately to stupor, coma, and death as the arterial PO 2
decreases below 4-5.3 kPa (30-40 mm Hg). Victims often are
unaware of this progression.
Cellular and Metabolic Effects. When the mitochondrial PO 2
falls
below ~ 0.13 kPa (1 mm Hg), aerobic metabolism stops, and the less
efficient anaerobic pathways of glycolysis become responsible for
the production of cellular energy. End products of anaerobic metabolism,
such as lactic acid, are released into the circulation in measurable
quantities. Energy-dependent ion pumps slow, and
transmembrane ion gradients dissipate. Intracellular concentrations
of Na + , Ca 2+ , and H + increase, finally leading to cell death. The time
course of cellular demise depends on the relative metabolic demands,
oxygen storage capacity, and anaerobic capacity of the individual
organs. Restoration of perfusion and oxygenation prior to hypoxic
cell death paradoxically can result in an accelerated form of cell
injury (ischemia–reperfusion syndrome), which is thought to result
from the generation of highly reactive oxygen free radicals.
Adaptation to Hypoxia. Long-term hypoxia results in adaptive
physiological changes; these have been studied most thoroughly in
persons exposed to high altitude. Adaptations include increased
numbers of pulmonary alveoli, increased concentrations of hemoglobin
in blood and myoglobin in muscle, and a decreased ventilatory
response to hypoxia. Short-term exposure to high altitude
produces similar adaptive changes. In susceptible individuals, however,
acute exposure to high altitude may produce acute mountain
sickness, a syndrome characterized by headache, nausea, dyspnea,
sleep disturbances, and impaired judgment progressing to pulmonary
and cerebral edema. Mountain sickness is treated with rest and analgesics
when mild or supplemental oxygen, descent to lower altitude,
or an increase in ambient pressure when more severe. Acetazolamide
(a carbonic anhydrase inhibitor) and dexamethasone also may be
helpful. The syndrome usually can be avoided by a slow ascent to
altitude, adequate hydration, and prophylactic use of acetazolamide
or dexamethasone.
Certain aspects of fetal and newborn physiology are strongly
reminiscent of adaptation mechanisms found in hypoxia-tolerant animals
(Mortola, 1999), including shifts in the oxyhemoglobin dissociation
curve (fetal hemoglobin), reductions in metabolic rate and
body temperature (hibernation-like mode), reductions in heart rate
and circulatory redistribution (as in diving mammals), and redirection
of energy utilization from growth to maintenance metabolism.
These adaptations probably account for the relative tolerance of the
fetus and neonate to both chronic (uterine insufficiency) and shortterm
hypoxia.
Oxygen Inhalation
Physiological Effects of Oxygen Inhalation. Oxygen
inhalation is used primarily to reverse or prevent the
development of hypoxia; other consequences usually
are minor. However, when O 2
is breathed in excessive
amounts or for prolonged periods, secondary physiological
changes and toxic effects can occur.
Respiratory System. Inhalation of O 2
at 1 atm or above causes a
small degree of respiratory depression in normal subjects, presumably
as a result of loss of tonic chemoreceptor activity. However,
ventilation typically increases within a few minutes of O 2
inhalation
because of a paradoxical increase in the tension of CO 2
in tissues.
This increase results from the increased concentration of oxyhemoglobin
in venous blood, which causes less efficient removal of carbon
dioxide from the tissues.
In a small number of patients whose respiratory center is
depressed by long-term retention of CO 2
, injury, or drugs, ventilation
is maintained largely by stimulation of carotid and aortic chemoreceptors,
commonly referred to as the hypoxic drive. The provision of
too much oxygen can depress this drive, resulting in respiratory acidosis.
In these cases, supplemental oxygen should be titrated carefully
to ensure adequate arterial saturation. If hypoventilation results,
then mechanical ventilatory support with or without tracheal intubation
should be provided.
Expansion of poorly ventilated alveoli is maintained in part
by the nitrogen content of alveolar gas; nitrogen is poorly soluble
and thus remains in the airspaces while oxygen is absorbed. High
oxygen concentrations delivered to poorly ventilated lung regions
dilute the nitrogen content and can promote absorption atelectasis,
occasionally resulting in an increase in shunt and a paradoxical worsening
of hypoxemia after a period of oxygen administration.
Cardiovascular System. Aside from reversing the effects of hypoxia,
the physiological consequences of oxygen inhalation on the cardiovascular
system are of little significance. Heart rate and cardiac output
are slightly reduced when 100% O 2
is breathed; blood pressure
changes little. While pulmonary arterial pressure changes little in
normal subjects with oxygen inhalation, elevated pulmonary artery
pressures in patients living at high altitude who have chronic hypoxic
pulmonary hypertension may reverse with oxygen therapy or return
to sea level. In particular, in neonates with congenital heart disease