Nicotinic effects acetylcholine

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. 

The tobacco compound nicotine has been used as an insecticide for over 200 years. It is especially effective against sucking insects, such as aphids, and has excellent contact activity. Related compounds are neonicotinoids (e.g., imidacloprid), which have similar insecticidal activity, but are less toxic to mammals. Nicotine and imidacloprid mimic the action of acetylcholine, which is the major excitatory neurotransmitter in an insect s central nervous system. The action of acetylcholine is stopped by the enzyme acetylcholinesterase, which rapidly breaks down acetylcholine. Nicotine and imidacloprid are also neuroexcitatory, but do so persistendy, since they are not affected by acetylcholinesterase. Overstimulation of the nervous system often leads to convulsions, paralysis, and death. 

Atropine is an antidotal treatment. It is used to reverse the muscarinic signs, but it will not reverse the nicotinic effects (muscular weakness, diaphragmatic weakness, etc.). Atropine blocks the effects of accumulated acetylcholine (ACh) at the synapse and should be continued until the nerve agent is metabohzed (Midthng et al, 1985). Over-atropinization can cause hyperthermia, tachycardia, agitation, mydriasis, and ileus, which can be life threatening in the horse (Meerstadt, 1982). 

Metrifonate, which is given orally, is effective in Schistosoma hematobium infections in three doses of 7.5-10 mg/kg 14 days apart. When metrifonate was used in daily doses, as in the treatment of Onchocerca volvulus infections, it produced muscarinic effects, and in one case there was proximal weakness due to a nicotinic effect. The combination of polyarthritis, fever, and a raised sedimentation rate was described in 11 of 34 patients treated. Metrifonate inhibits blood cholinesterase activity for up to 48 hours, and common reactions that probably result from this effect comprise nausea, vomiting, abdominal pain, diarrhea, dizziness, weakness, headache, and muscle cramps. Because of its prolonged inhibition of brain cholinesterase and increased steady-state concentrations of acetylcholine in the cortex and the hippocampus, it is now also increasingly used in the treatment of Alzheimer s disease. 

The clinical signs of excess acetylcholine at nerve endings mimic hyperactivity of the parasympathetic nervous system. Signs relative to the alimentary tract include excess salivation, lacrimation, abdominal pain, vomiting, intestinal hypermotility, and diarrhea. The muscarinic effects of acetylcholine cause bronchoconstriction and an increase in bronchial secretions. The nicotinic effects of acetylcholine consist of involuntary irregular, violent muscle contractions and weakness of voluntary muscles. Death occurs as a result of respiratory failure. 

Schueler (267) suggested that the muscarinic and nicotinic effects of acetylcholine are mediated by different conformers of the flexible molecule, and he evaluated structures ( )-(222)("transoid")and (223)("cisoid")as examples of analogs of conformational extremes of acetylcholine. 

A series of mineral esters of choline have also been prepared. Nitro-choline is as active as acetylcholine (2, 6,14,15). Nitrosocholine possesses nicotinic effects, but mainly a muscarinic action (2). 

In 1914, Dale defined two subdivisions of the parasympathetic nervous system when he observed that ethers and esters (including acetylcholine) of choline produced effects similar to those of muscarine (muscarinic effects) or nicotine (nicotinic effects) (2). The initial experiments were performed using an ergot extract contaminated with acetylcholine, although Dale was unaware of this contamination. Ewins, a chemist who collaborated with Dale, isolated acetylcholine from the ergot extract and subsequently synthesized acetylcholine, thus allowing Dale to show that the unexpected muscarinic effects observed with the ergot preparation were the result of acetylcholine. He proposed the term "parasympathomimetic" to describe ... 

Another means of producing a cholinergic response is to interfere with the mechanism by which the action of acetylcholine is terminated. Thus, inhibition of its rapid hydrolysis by AChE increases the concentration of acetylcholine in the synapse and results in production of both muscarinic and nicotinic effects. 

Paraoxon reduces the cardiac output of cats. This is not tractable to treatment with methylatropine, but does respond to both PAM and obidoxime [225]. This effect is not therefore related to peripheral muscarinic hyperactivity at vagal nerve endings, but is more likely related to a potentiation of the nicotinic effects of acetylcholine at parasympathetic ganglia. 

---