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

272 and its metabolites are eliminated rapidly by the kidney. The rate of
urinary excretion of nicotine diminishes when the urine is alkaline.
Nicotine also is excreted in the milk of lactating women who smoke;
the milk of heavy smokers may contain 0.5 mg/L.
SECTION II
NEUROPHARMACOLOGY
Acute Nicotine Poisoning. Poisoning from nicotine may occur from
accidental ingestion of nicotine-containing insecticide sprays or in
children from ingestion of tobacco products. The acutely fatal dose
of nicotine for an adult is probably ~ 60 mg. Smoking tobacco usually
contains 1-2% nicotine. Apparently, the gastric absorption of
nicotine from tobacco taken by mouth is delayed because of slowed
gastric emptying, so vomiting caused by the central effect of the initially
absorbed fraction may remove much of the tobacco remaining
in the GI tract.
The onset of symptoms of acute, severe nicotine poisoning
is rapid; they include nausea, salivation, abdominal pain, vomiting,
diarrhea, cold sweat, headache, dizziness, disturbed hearing and
vision, mental confusion, and marked weakness. Faintness and prostration
ensue; the blood pressure falls; breathing is difficult; the pulse
is weak, rapid, and irregular; and collapse may be followed by terminal
convulsions. Death may result within a few minutes from respiratory
failure.
Therapy. Vomiting may be induced, or gastric lavage should be performed.
Alkaline solutions should be avoided. A slurry of activated
charcoal is then passed through the tube and left in the stomach.
Respiratory assistance and treatment of shock may be necessary.
Smoking Cessation. Two goals of the pharmacotherapy of smoking
cessation are the reduction of the craving for nicotine and inhibition
of the reinforcing effects of nicotine. Myriad approaches and
drug regimens are used, including nicotine replacement, bupropion
(Chapter 15), and nicotinic ACh receptor agonists (Chapters 15 and
24 and the review by Frishman, 2009). Nicotine dependence is likely
mediated, at least in part, by subtypes of the neuronal nicotinic
acetylcholine receptor (N n
). The mesolimbic α 4
β 2
subtype of N n
and
α 4
β 2
-stimulated release of dopamine seem to play major roles in
nicotine dependence. Thus, one aim of drug development in this area
is discovery of an agent that will stimulate α 4
β 2
-mediated DA release
sufficiently to reduce craving during periods of abstinence from
smoking yet occupy the α 4
β 2
N n
receptor sufficiently to inhibit nicotine
reinforcement during smoking (Rollema et al., 2007).
Varenicline (CHANTIX) has been recently introduced as an aid
to smoking cessation. The drug interacts with nicotinic ACh receptors.
In model systems, varenicline is a partial agonist at α 4
β 2
receptors
and a full agonist at the α 7
subtype, with weak activity toward
α 3
β 2
- and α 6
-containing receptors (Mihalak et al., 2006). The drug
is effective clinically; however, it is not benign: Based on postmarketing
studies, the FDA has issued a warning about mood and
behavioral changes associated with its use (Frishman, 2009).
Nicotine itself is available in several dosage forms to help
achieve abstinence from tobacco use. Efficacy results primarily from
preventing a withdrawal or abstinence syndrome. Nicotine is marketed
for over-the-counter use as a gum or lozenge (NICOTINE
POLACRILEX, NICORETTE, COMMIT, THRIVE, others), transdermal patch
(NICODERM, HABITROL, others), a nasal spray (NICOTROL), or a vapor
inhaler (NICOTROL). The gum and transdermal systems are used most
widely, and the objective is to obtain a sustained plasma nicotine
concentration lower than venous blood concentrations after smoking.
Arterial blood concentrations immediately following inhalation can
be as much as 10-fold higher than venous concentrations. The efficacy
of these dosage forms in producing abstinence from smoking
is enhanced when linked to counseling and motivational therapy
(Benowitz, 1999; Fant et al., 1999; Frishman, 2009).
GANGLIONIC BLOCKING DRUGS
There are two categories of agents that block ganglionic
nicotinic receptors. The prototype of the first group,
nicotine, initially stimulates the ganglia by an ACh-like
action and then blocks them by causing a persistent
depolarization (Volle, 1980). Compounds in the second
category (e.g., trimethaphan and hexamethonium)
impair transmission either by competing with ACh for
ganglionic nicotinic receptor sites or by blocking the
channel. Trimethaphan acts by competition with ACh,
analogous to the mechanism of action of curare at the
neuromuscular junction. Hexamethonium appears to
block the channel after it opens; this action shortens the
duration of current flow because the open channel
either becomes occluded or closes (Gurney and Rang,
1984). Regardless of the mechanism, the initial EPSP is
blocked, and ganglionic transmission is inhibited. The
chemical diversity of compounds that block autonomic
ganglia without causing prior stimulation is shown in
Figure 11–7.
Ganglionic blocking agents such as mecamylamine
(INVERSINE) and trimethaphan were the first
effective therapy for the treatment of hypertension and
were used extensively during the 1950s and 1960s, as
described in earlier editions of this text. However, due
to the role of ganglionic transmission in both sympathetic
and parasympathetic neurotransmission, the antihypertensive
action of ganglionic blocking agents was
accompanied by numerous undesirable side effects.
History and Structure-Activity Relationship. Although Marshall
first described the “nicotine-paralyzing” action of tetraethylammonium
(TEA) on ganglia in 1913, TEA was largely overlooked until
the effects of the ion on the cardiovascular system and autonomic
ganglia were analyzed. The prototypical ganglionic blocking drug
in this series, hexamethonium (C6), has a bridge of six methylene
groups between the two quaternary nitrogen atoms (Figure 11–7). It
has minimal neuromuscular and muscarinic blocking activities.
Triethylsulfoniums (e.g., trimethaphan), like the quaternary and bisquaternary
ammonium ions, possess ganglionic blocking actions
(Figure 11–7). Mecamylamine, a secondary amine, is currently
licensed as an orphan drug for Tourette’s syndrome.
Pharmacological Properties. Nearly all the physiological alterations
observed after the administration of ganglionic blocking agents can
be anticipated with reasonable accuracy by a careful inspection of
Figure 8–1 and Table 8–1, and by knowing which division of the