History
A 58-year old woman who drank
alcohol daily for two decades (met criteria for alcohol
dependence listed in the fourth edition of the Diagnostic and
Statistical Manual of Mental Disorders) was taking oxazepam (Serax)
at a daily dose of 20 - 30 mg for anxiety. No evidence of
alcohol myopathy or polyneuropathy was found. The patient's
primary pulmonary hypertension required bilateral sequential
lung transplantation. After receiving nitric oxide as a
pulmonary dilator postoperatively for 15 days, she was found
to be paralyzed and areflexic in all four extremities.
Cranial-nerve motor function
was normal. Electromyography revealed extensive denervation.
Metabolic, endocrinologic, toxic, and infectious causes were
ruled out. The patient's creatinine kinase concentration was
normal, and she did not have myoglobulinemia. The neurological
consultant diagnosed a neuropathy of indeterminate cause. The
patient required tracheostomy and mechanical ventilation. Her
muscles improved gradually over a period of three months.
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Diagnosis
a) The hypothetical
mechanism of this lower motor neuron disorder is an
interaction between nitric oxide, used for the treatment of
pulmonary hypertension, and alcohol. Mechanism: Nitric oxide
activates guanylate cyclase, which is involved in
transduction of the glutamatergic NMDA-type receptor.
Glutamate (and other excitatory amino acids) can damage
neurons if they excessively or continuously stimulate their
receptors. This excitotoxic mechanism has been implicated in
several neurodegenerative motor neuron diseases (e.g.,
amyotrophic lateral sclerosis, Guam motor neuron disease) as
well as in other pathological states (ischemia, stroke,
epilepsy). NMDA type of excitatory transmission has been
found as one of the main targets of clinically relevant
concentrations of ethanol (depression of transmission;
reviewed in Tsai et al, Am J Psychiatry 152: 332, 1995). Of
particular interest is that this transmission is exaggerated
in withdrawal state (animal experimental data): rebound
excitation in withdrawal could be explained by this
mechanism. Other studies show increase in receptor number
after ethanol withdrawal (in experimental animal models).
This up-regulation may render motor neurons more susceptible
to excitotoxic insults, including over exposure to nitric
oxide.
b) Nitric oxide has been
found as selective and effective pulmonary vasodilator.
Inhaled NO (40 ppm in air) decreases significantly pulmonary
vascular resistance (PVR) but not the systemic vascular
resistance (SVR) (Pepke-Zaba et al. Lancet 338: 1173, 1991).
This contrast with an equally (or more ..) effective
decrease of PVR by prostacyclin PGI2 that however also
decreases SVR to the same extent. Thus vasodilatory effect
of inhaled NO is restricted to the abluminal surface of the
pulmonary vasculature. For the the mechanism of NO
vasodilation, see the attached figure (from Moncada &
Higgs, NEJM, 329:2002, 1993)
c) There are problems with
the above hypothesis: i) If NO is known to be quickly
neutralized, i.e., mainly scavenged by hemoglobin, how that
it can interact with only one part of the nervous system
(lower motor neurons). Although there is evidence that that
NO can be stored and functionally reactivated at a site away
of its production (or delivery) the specificity of damage in
this case is still puzzling. ii) there is no evidence of
up-regulation of NMDA in human, an in particular in this
patient.
GABAergic inhibition has
been recognized as the specific target of ethanol action:
ethanol in clinically relevant concentrations potentiates
inhibitory transmission in the CNS (experimental data on
animals). There is evidence of a specific site on
GABA-benzodiazepni (BDZ) complex where ethanol and several
BDZ partial inverse agonist interact. One of these
compounds, Ro 15-4513, has been found to antagonize ethanol
effects in animal experiments. For the moment this site is
of no relevance for clinical pharmacology. Research in this
direction has been apparently suppressed for fear that an
ethanol antagonist may contribute to an increase in drinking
behavior.... See also the tables in the syllabus, p. 559,
566.
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Development
This patient recovered
spontaneously without any treatment. The point to emphasize is
that the administration of nitric oxide should be avoided in
patients with enhanced glutamatergic transmission states, such as
ischemia, stroke, epilepsy, or, as is in this case, chronic
alcohol consumption.
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