Toxicity nicotinic effects

It soon became evident that no available antidotes could block the pharmacologic activity of these chemicals, alleviate the signs and symptoms of toxicity, or restore normal bodily functions after exposure. Atropine readily antagonized the muscarinic actions, including those in the central nervous system (CNS), but elicited no reversal of the nicotinic effects. Better forms of therapy were sought, particularly to alleviate the nicotinic effects of anticholinesterase agents. 

A. There are no known health problems from oral Salvia use. However, it is known that smoking tobacco is damaging to your lungs and may cause cancer, emphysema, bronchitis, stroke and cardiovascular disease. These toxic side-effects of tobacco smoking are not due mainly to nicotine but rather to combustion products (tars and carbon monoxide), which are present whenever any type of plant material (e.g. Salvia) is smoked. Common sense will tell you that smoking Salvia, or any material, can be bad for your health. It is not known if Salvia can cause birth defects, but it is prudent to assume that it could. 

Epibatidine was shown to be a very potent and selective agonistic ligand of nicotinic acetylcholine receptors. This natural product is effective in various animal models of pain through a pronounced nAChR agonistic mechanism (Ki <100 pm) which is accompanied by severe and nACh-related side-effects (Corey et al. 1993 Rupniak et al., 1994 Boyce et al., 2000). A clear differentiation between antinociceptive activity in animal models of pain and toxic side-effects cannot be determined. Nevertheless there is some activity directed towards the development of epibatidine as an analgesic (Bai et al., 1997). 

Carbamates effect the reversible carbamylation of acetylcholinesterase, permitting accumulation of acetylcholine at cholinergic neuroeffector junctions (muscarinic effects), at the myoneural junctions of skeletal muscle, and in the autonomic ganglia (nicotinic effects). CNS function is also impaired. However the relatively large dissociation constant of the carbamyl-enzyme complex indicates that it dissociates more readily than does the organophosphate-enzyme complex, mitigating the toxicity of the carbamate pesticides. The reversibility of the carbamyl-enzyme complex affects (limits) the utility of blood enzyme measurements as a diagnostic tool. 

A combination of atropine sulfate and magnesium sulfate protects rabbits against the toxic effects of Lsofluorphatc. Atropine sulfate counteracts the mu.scarinic effect, and magnesium sulfate counteracts the nicotinic effect of the drug." Isofluorphate has been used in the treatment of glaucoma. 

Poison hemlock toxicity has effects similar to those of nicotine. The alkaloid content varies significantly between species, plant parts, and geographic location. The alkaloid concentration increases in all parts as the plant matures but remains the highest in the roots. Initial CNS stimulation, nausea, vomiting, and sore throat are followed by cardiorespiratory depression and ascending paralysis. 

Pyridostigmine bromide studies have been performed in dogs, guinea pigs, monkeys, rabbits, rats, and mice. Diarrhea, salivation, tremors, and respiratory failure were seen prior to death. Side effects of the drug are related to muscarinic and nicotinic effects. Toxicity is also related to cholinergic stimulation. Effectiveness of pretreatment to reduce lethality after exposure to nerve agents (in particular, soman) is dependent on the administration of atropine and pralidoxime, postexposure. 

Toxic effects occur within seconds to 5 min of nerve agent vapor or aerosol inhalation. The muscarinic effects include ocular (miosis, conjunctival congestion, ciliary spasm), nasal discharge, respiratory (bronchoconstriction and increased bronchial secretion), gastrointestinal (anorexia, vomiting, abdominal cramps, and diarrhea), sweating, salivation, and cardiovascular (bradycardia and hypotension) effects. The nicotinic effects include muscular fa-sciculation and paralysis. CNS effects can include ataxia, confusion, loss of reflexes, slurred speech, coma, and paralysis. 

Some references indicate that prahdoxime should be avoided in the treatment of carbamate (another type of anticholinesterase insecticide) poisoning because of reports of worsened toxicity in animals. Prahdoxime may be considered when exposure to carbamates is not known but an anticholinesterase is suspected based on symptoms or when respiratory paralysis due to nicotinic effects is not managed sufficiently by mechanical ventilation. 

In spite of its extreme toxicity, nicotine remains one of the safest horticultural insecticides, provided correct precautions are taken. As it is volatile it has no persistent effect and cannot give rise to lethal chain reactions such as those which may occur with the chlorinated hydrocarbons. 

Nicotinic toxicity Nicotine is commonly used in the form of chewing gum and transder-mal patches by smokers trying to kick the habit and is still used also in some insecticides. Toxic effects include CNS stimulation (including convulsions), ganglionic stimulation, and neuromuscular end plate depolarization leading to fasciculations and paralysis. 

Ophthalmic effects due to direct ocular exposure to OPs include optic neuropathy, retinal degeneration, defective vertical smooth pursuit, myopia, and miosis. Respiratory effects, including muscarinic, nicotinic, and central effects, contribute to respiratory distress in acute and delayed OP toxicity, Muscarinic effects, such as bronchospasm and laiyngeal spasm, can lead to airway obstruction. Nicotinic effects can lead to weakness and paralysis of respiratory oropharyngeal tiiuscles. Central effects can lead to cessation of respiration. 

Well-known symptoms of sarin toxicity include miosis, hypersecretions, bradycardia, and fasciculations. However, the mechanism of organophosphate toxicity seems to involve conflicting actions. For example, mydriasis or miosis, and bradycardia or tachycardia may occur. Acute respiratory insufficiency is the most important cause of immediate death. Early symptoms include (i) tachypnea due to increased airway secretions and bronchospasm (a muscarinic effect), (ii) peripheral respiratory muscle paralysis (a nicotinic effect), and (iii) inhibition of respiratory centers (a CNS effect), all of which lead to severe respiratory deficiency. If left untreated at this stage, death will result. Cardiovascular symptoms may include hypertension or hypotension. Various arrhythmias can also occur, and caution is required when the QT interval is prolonged. In particular, if hypoxemia is present, fatal arrhythmias may occur with intravenous administration of atropine... 

It is known that human exposure to organophosphorus compounds can result in a variety of acute toxic effects. These arise primarily as a result of the inhibition of acetylcholinesterase. Signs of acute toxicity are due to effects on the central nervous system (anxiety, ataxia, hypotension), to muscarinic effects (wheezing, cough, rhinitis) and to nicotinic effects (muscle weakness, mydriasis and tachycardia). Other acute effects include chest tightness, abdominal cramps, confusion and convulsions. With some organophosphorus compounds, a specific syndrome may develop. This is delayed peripheral neuropathy or OP-induced delayed neuropathy (OPIDN). (For a more detailed discussion on the toxicity of organophosphorus compounds see Chapter 10.)... 

Of the water-soluble vitamins, intakes of nicotinic acid [59-67-6] on the order of 10 to 30 times the recommended daily allowance (RE)A) have been shown to cause flushing, headache, nausea, and moderate lowering of semm cholesterol with concurrent increases in semm glucose. Toxic levels of foHc acid [59-30-3] are ca 20 mg/d in infants, and probably approach 400 mg/d in adults. The body seems able to tolerate very large intakes of ascorbic acid [50-81-7] (vitamin C) without iH effect, but levels in excess of 9 g/d have been reported to cause increases in urinary oxaHc acid excretion. Urinary and blood uric acid also rise as a result of high intakes of ascorbic acid, and these factors may increase the tendency for formation of kidney or bladder stones. AH other water-soluble vitamins possess an even wider margin of safety and present no practical problem (82). 

Despite stmctural similarities, the pharmacological consequences of excesses of these substances are quite different. Due to the interest in the effects of nicotinic acid on atherosclerosis, and in particular its use based on its abiUty to lower semm cholesterol, the toxicity of large doses of nicotinic acid has been evaluated. Eor example, in a study designed to assess its abiUty to lower semm cholesterol, only 28% of the patients remained in the study after receiving a large initial dose of 4 g of nicotinic acid due to intolerance at these large doses (70). 

Mayer and coworkers128 discovered that kojic acid is a moderately effective activator for nicotine insecticides. When tested against the melon worm (Diaphania hyalinata L.) and the southern armyworm (Prodenia eridania Cram.), kojic acid (alone) was not toxic but the toxicity of a 5% nicotine sulfate-pyrophyllite dust was increased 35 %, and that of a 5 % nicotine bentonite-bentonite spray by some 50%, by the addition of 5% of kojic... 

The essence of ChR action consists in dephosphorylation of the enzyme inhibited, which becomes apparent as restoration of its activity, i.e. ability to perform enzymatic hydrolysis. Therapeutic efficacy of ChR is associated with their capability to eliminate toxic effects of anticholinesterases on nicotine receptors. 

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