Page 134 - Basic _ Clinical Pharmacology ( PDFDrive )

120 SECTION II Autonomic Drugs

overcome by increasing the amount of endogenous acetylcholine The European Commission imposed a 2-year ban on certain neo-
at the neuroeffector junctions. Theoretically, a cholinesterase nicotinoids (clothianidin, imidacloprid, thiamethoxam) in 2013.
inhibitor could be used to reverse these effects. Physostigmine has Their use remains restricted in the European Union until a review
been used for this application because it enters the central nervous of this policy’s effects is completed in January 2017. As of Janu-
system and reverses the central as well as the peripheral signs of ary 2016, the US Fish and Wildlife Service banned neonicotinoid
muscarinic blockade. However, as described below, physostigmine use in wildlife refuges. Neonicotinoids are suspected to contrib-
itself can produce dangerous central nervous system effects, and ute to colony collapse disorder because they suppress immunity
such therapy is therefore used only in patients with dangerous against bee pathogens including the mite (Varroa destructor) that
elevation of body temperature or very rapid supraventricular also serves as a vector for viruses and the Nosema species of fungi
tachycardia (see also Chapter 58). that parasitize the gut of bees. Research to ascertain the effect of
neonicotinoids on pollinators such as bees and butterflies requires
F. Central Nervous System carefully controlled conditions. Neonicotinoid residues have a
Tacrine was the first drug with anticholinesterase and other cho- long half-life (5 months to 3 years) in the soil, and because they
linomimetic actions used for the treatment of mild to moderate are systemic and enter the plant stem, leaves, and flowers, they
Alzheimer’s disease. Tacrine’s efficacy is slight, and hepatic toxicity can present a long-lasting hazard to pollinators. The Australian
is significant. Donepezil, galantamine, and rivastigmine are newer, government’s report on neonicotinoids and honey bees recounts
more selective acetylcholinesterase inhibitors that appear to have that Australia is one of a few countries that lack Varroa, which
the same marginal clinical benefit as tacrine but with less toxic- therefore provides an opportunity to test neonicotinoids in the
ity in treatment of cognitive dysfunction in Alzheimer’s patients. absence of compounds used to treat this mite that contributes to
Donepezil may be given once daily because of its long half-life, bee pathology.
and it lacks the hepatotoxic effect of tacrine. However, no trials
comparing these newer drugs with tacrine have been reported. 1. Acute toxicity—The fatal dose of nicotine is approximately
These drugs are discussed in Chapter 60. 40 mg, or 1 drop of the pure liquid. This is the amount of nico-
tine in two regular cigarettes. Fortunately, most of the nicotine in
cigarettes is destroyed by burning or escapes via the “sidestream”
Toxicity smoke. Ingestion of nicotine insecticides or of tobacco by infants
The toxic potential of the cholinoceptor stimulants varies mark- and children is usually followed by vomiting, limiting the amount
edly depending on their absorption, access to the central nervous of the alkaloid absorbed.
system, and metabolism. The toxic effects of a large dose of nicotine are simple exten-
sions of the effects described previously. The most dangerous are
A. Direct-Acting Muscarinic Stimulants (1) central stimulant actions, which cause convulsions and may
Drugs such as pilocarpine and the choline esters cause predictable progress to coma and respiratory arrest; (2) skeletal muscle end
plate depolarization, which may lead to depolarization block-
signs of muscarinic excess when given in overdosage. These effects ade and respiratory paralysis; and (3) hypertension and cardiac
include nausea, vomiting, diarrhea, urinary urgency, salivation, arrhythmias.
sweating, cutaneous vasodilation, and bronchial constriction. The Treatment of acute nicotine poisoning is largely symptom-
effects are all blocked competitively by atropine and its congeners. directed. Muscarinic excess resulting from parasympathetic
Certain mushrooms, especially those of the genus Inocybe, con-
tain muscarinic alkaloids. Ingestion of these mushrooms causes ganglion stimulation can be controlled with atropine. Central
stimulation is usually treated with parenteral anticonvulsants
typical signs of muscarinic excess within 15–30 minutes. These such as diazepam. Neuromuscular blockade is not respon-
effects can be very uncomfortable but are rarely fatal. Treatment sive to pharmacologic treatment and may require mechanical
is with atropine, 1–2 mg parenterally. (Amanita muscaria, the ventilation.
first source of muscarine, contains very low concentrations of the Fortunately, nicotine is metabolized and excreted relatively
alkaloid.)
rapidly. Patients who survive the first 4 hours usually recover
completely if hypoxia and brain damage have not occurred.
B. Direct-Acting Nicotinic Stimulants
Nicotine itself is the only common cause of this type of poisoning. 2. Chronic nicotine toxicity—The health costs of tobacco
(Varenicline toxicity is discussed elsewhere in this chapter.) The smoking to the smoker and its socioeconomic costs to the general
acute toxicity of the alkaloid is well defined but much less impor- public are still incompletely understood. However, the 1979 Sur-
tant than the chronic effects associated with smoking. Nicotine was geon General’s Report on Health Promotion and Disease Prevention
also used in insecticides but has been replaced by neonicotinoids, stated that “cigarette smoking is clearly the largest single prevent-
synthetic compounds that resemble nicotine only partially in struc- able cause of illness and premature death in the United States.”
ture. As nicotinic receptor agonists, neonicotinoids are more toxic This statement has been supported by numerous subsequent
for insects than for vertebrates. This advantage led to their wide- studies. Unfortunately, the fact that the most important of the
spread agricultural use to protect crops. However, there is concern tobacco-associated diseases are delayed in onset reduces the health
about the role of neonicotinoids in the collapse of bee colonies. incentive to stop smoking.