Page 135 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 7 Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs 121

Clearly, the addictive power of cigarettes is directly related to slowly or rapidly developing symptoms, as described in the Case
their nicotine content. It is not known to what extent nicotine Study, which persist for days. The cholinesterase inhibitors used as
per se contributes to the other well-documented adverse effects of chemical warfare agents (soman, sarin, VX) induce effects rapidly
chronic tobacco use. It is highly probable that nicotine contributes because of the large concentrations present.
to the increased risk of vascular disease and sudden coronary death Acute intoxication must be recognized and treated promptly in
associated with smoking. In addition, nicotine probably contrib- patients with heavy exposure. The dominant initial signs are those
utes to the high incidence of ulcer recurrences in smokers with of muscarinic excess: miosis, salivation, sweating, bronchial constric-
peptic ulcer. These effects of smoking are not avoided by the use of tion, vomiting, and diarrhea. Central nervous system involvement
electronic cigarettes (“vaping”) since only the nonnicotine compo- (cognitive disturbances, convulsions, and coma) usually follows
nents (“tars”) of tobacco are eliminated. rapidly, accompanied by peripheral nicotinic effects, especially
There are several approaches to help patients stop smoking. depolarizing neuromuscular blockade. Therapy always includes
One approach is replacement therapy with nicotine in the form (1) maintenance of vital signs—respiration in particular may be
of gum, transdermal patch, nasal spray, or inhaler. All these forms impaired; (2) decontamination to prevent further absorption—this
have low abuse potential and are effective in patients motivated to may require removal of all clothing and washing of the skin in cases
stop smoking. Their action derives from slow absorption of nico- of exposure to dusts and sprays; and (3) atropine parenterally in large
tine that occupies α4β2 receptors in the central nervous system doses, given as often as required to control signs of muscarinic excess.
and reduces the desire to smoke and the pleasurable feelings of Therapy often also includes treatment with pralidoxime, as described
smoking. in Chapter 8, and administration of benzodiazepines for seizures.
Another quite effective agent for smoking cessation is vareni- Preventive therapy for cholinesterase inhibitors used as chemi-
cline, a synthetic drug with partial agonist action at α4β2 nicotinic cal warfare agents has been developed to protect soldiers and
receptors. Varenicline also has antagonist properties that persist civilians. Personnel are given autoinjection syringes containing
because of its long half-life and high affinity for the receptor; this a carbamate, pyridostigmine, and atropine. Protection is pro-
prevents the stimulant effect of nicotine at presynaptic α4β2 recep- vided by pyridostigmine, which, by prior binding to the enzyme,
tors that causes release of dopamine. However, its use is limited by impedes binding of organophosphate agents and thereby prevents
nausea and insomnia and also by exacerbation of psychiatric ill- prolonged inhibition of cholinesterase. The protection is limited
nesses, including anxiety and depression. The incidence of adverse to the peripheral nervous system because pyridostigmine does not
neuropsychiatric and cardiovascular events is reportedly low yet readily enter the central nervous system. Enzyme inhibition by
post-marketing surveillance continues. The efficacy of varenicline is pyridostigmine dissipates within hours (Table 7–4), a duration
superior to that of bupropion, an antidepressant (see Chapter 30). of time that allows clearance of the organophosphate agent from
Some of bupropion’s efficacy in smoking cessation therapy stems the body.
from its noncompetitive antagonism (see Chapter 2) of nicotinic Chronic exposure to certain organophosphate compounds,
receptors where it displays some selectivity among neuronal including some organophosphate cholinesterase inhibitors, causes
subtypes. delayed neuropathy associated with demyelination of axons. Trior-
thocresyl phosphate, an additive in lubricating oils, is the proto-
C. Cholinesterase Inhibitors type agent of this class. The effects are not caused by cholinesterase
The acute toxic effects of the cholinesterase inhibitors, like inhibition but rather by inhibition of neuropathy target esterase
those of the direct-acting agents, are direct extensions of their (NTE) whose symptoms (weakness of upper and lower extremities,
pharmacologic actions. The major source of such intoxications unsteady gait) appear 1–2 weeks after exposure. Another nerve tox-
is pesticide use in agriculture and in the home. Approximately icity called intermediate syndrome occurs 1–4 days after exposure
100 organophosphate and 20 carbamate cholinesterase inhibi- to organophosphate insecticides. This syndrome is also character-
tors are available in pesticides and veterinary vermifuges used in ized by muscle weakness; its origin is not known but it appears to
the USA. Cholinesterase inhibitors used in agriculture can cause be related to cholinesterase inhibition.