Page 412 - Basic _ Clinical Pharmacology ( PDFDrive )

398 SECTION V Drugs That Act in the Central Nervous System

clearance of other drugs eliminated by the cytochrome P450s that intoxicated with a blood alcohol concentration of 300–400 mg/dL
constitute the MEOS system, and in the generation of the toxic (0.30-0.40%), whereas this level is associated with marked
byproducts of cytochrome P450 reactions (toxins, free radicals, intoxication or even coma in a nontolerant individual. The pro-
H O ). pensity of moderate doses of alcohol to inhibit the attention and
2
2
information-processing skills as well as the motor skills required
C. Acetaldehyde Metabolism for operation of motor vehicles has profound effects. Approxi-
Much of the acetaldehyde formed from alcohol is oxidized in the mately 30–40% of all traffic accidents resulting in a fatality in the
liver in a reaction catalyzed by mitochondrial NAD-dependent United States involve at least one person with blood alcohol near
aldehyde dehydrogenase (ALDH). The product of this reaction is or above the legal level of intoxication, and drunken driving is a
acetate (Figure 23–1), which can be further metabolized to CO leading cause of death in young adults.
2
and water, or used to form acetyl-CoA. Like other sedative-hypnotic drugs, alcohol is a CNS depres-
Oxidation of acetaldehyde is inhibited by disulfiram, a drug sant. At high blood concentrations, it induces coma, respiratory
that has been used to deter drinking by patients with alcohol depression, and death.
dependence. When ethanol is consumed in the presence of disul- Ethanol affects a large number of membrane proteins that
firam, acetaldehyde accumulates and causes an unpleasant reac- participate in signaling pathways, including neurotransmitter recep-
tion of facial flushing, nausea, vomiting, dizziness, and headache. tors for amines, amino acids, opioids, and neuropeptides; enzymes
+
+
Several other drugs (eg, metronidazole, cefotetan, trimethoprim) such as Na /K -ATPase, adenylyl cyclase, phosphoinositide-specific
inhibit ALDH and have been claimed to cause a disulfiram-like phospholipase C; a nucleoside transporter; and ion channels. Much
reaction if combined with ethanol. attention has focused on alcohol’s effects on neurotransmission by
Some people, primarily of East Asian descent, have genetic glutamate and γ-aminobutyric acid (GABA), the main excitatory
deficiency in the activity of the mitochondrial form of ALDH, and inhibitory neurotransmitters in the CNS. Acute ethanol expo-
which is encoded by the ALDH2 gene. When these individuals sure enhances the action of GABA at GABA receptors, which is
A
drink alcohol, they develop high blood acetaldehyde concentra- consistent with the ability of GABA-mimetics to intensify many of
tions and experience a noxious reaction similar to that seen with the acute effects of alcohol and of GABA antagonists to attenu-
A
the combination of disulfiram and ethanol. This form of reduced- ate some of the actions of ethanol. Ethanol inhibits the ability of
activity ALDH is strongly protective against alcohol-use disorders. glutamate to open the cation channel associated with the N-methyl-
d-aspartate (NMDA) subtype of glutamate receptors. The NMDA
Pharmacodynamics of Acute Ethanol receptor is implicated in many aspects of cognitive function,
including learning and memory. “Blackouts”—periods of memory
Consumption loss that occur with high levels of alcohol—may result from inhibi-
A. Central Nervous System tion of NMDA receptor activation. Experiments that use modern
The CNS is markedly affected by acute alcohol consumption. genetic approaches eventually will yield a more precise definition
Alcohol causes sedation, relief of anxiety and, at higher concentra- of ethanol’s direct and indirect targets. In recent years, experiments
tions, slurred speech, ataxia, impaired judgment, and disinhibited with mutant strains of mice, worms, and flies have reinforced the
behavior, a condition usually called intoxication or drunkenness importance of previously identified targets and helped identify
(Table 23–1). These CNS effects are most marked as the blood new candidates, including a calcium-regulated and voltage-gated
level is rising, because acute tolerance to the effects of alcohol potassium channel that may be one of ethanol’s direct targets (see
occurs after a few hours of drinking. For chronic drinkers who Box: What Can Drunken Worms, Flies, and Mice Tell Us about
are tolerant to the effects of alcohol, higher concentrations Alcohol?).
are needed to elicit these CNS effects. For example, an indi-
vidual with chronic alcoholism may appear sober or only slightly B. Heart
Significant depression of myocardial contractility has been
observed in individuals who acutely consume moderate amounts
TABLE 23–1 Blood alcohol concentration (BAC) and of alcohol, ie, at a blood concentration above 100 mg/dL.
clinical effects in nontolerant individuals.
C. Smooth Muscle
BAC (mg/dL) 1 Clinical Effect
Ethanol is a vasodilator, probably as a result of both CNS effects
50–100 Sedation, subjective “high,” slower reaction times (depression of the vasomotor center) and direct smooth muscle
100–200 Impaired motor function, slurred speech, ataxia relaxation caused by its metabolite, acetaldehyde. In cases of severe
200–300 Emesis, stupor overdose, hypothermia—caused by vasodilation—may be marked
300–400 Coma in cold environments. Preliminary evidence indicates that fliban-
serin augments the hypotensive effects of ethanol and may cause
>400 Respiratory depression, death
severe orthostatic hypotension and syncope (see Chapter 16).
1 In many parts of the United States, a blood level above 80–100 mg/dL for adults or Ethanol also relaxes the uterus and—before the introduction of
5–20 mg/dL for persons under 21 is sufficient for conviction of driving while “under
the influence.” more effective and safer uterine relaxants (eg, calcium channel