Nicotine sites

The central nervous system contains both muscarinic and nicotinic receptors, the brain being relatively richer in muscarinic sites and the spinal cord containing a preponderance of nicotinic sites. The physiologic roles of these receptors are discussed in Chapter 21. 

General supportive care should be provided as outlined above. Extra precautions should be taken to ensure that rescuers and health care providers are not poisoned by exposure to contaminated clothing or skin. This is especially critical for the most potent substances such as parathion or nerve gas agents. Antidotal treatment consists of atropine and pralidoxime (see Table 58-4). Atropine is an effective competitive inhibitor at muscarinic sites but has no effect at nicotinic sites. Pralidoxime given early enough is capable of restoring the cholinesterase activity and is active at both muscarinic and nicotinic sites. 

Actions Physostigmine has a wide range of actions because it stimulates not only muscarinic and nicotinic sites of the autonomic nervous system but also the nicotinic receptors of the neuromuscular junction. Its duration of action is about 2-4 hours. Physostigmine can enter and stimulate the CNS. 

The West Discovers Tobacco Tobacco as Panacea From Panacea to Panned Prevalence of Tobacco Use Smoking in the United States Initiation of Smoking Smokeless Tobacco Use Pharmacology of Nicotine Sites of Action Pharmacokinetics Tolerance and Dependence Tolerance... 

The R-enantiomer of the pyridylquinucli-dine (62)has a slightly higher affinity for nicotinic sites than the S-enantiomer (109). 

Therefore, the inclusion of an electron donating group such as the amino group has greatly increased the chemical and enzymatic stability of our cholinergic agonist. Unfortunately, it is found that carbachol shows very little selectivity between the muscarinic and nicotinic sites. 

Clinically, the main benefit of oximes is to reverse cholinergic effects at peripheral nicotinic sites so that, for example, muscle strength may improve. Oximes are much less effective than atropine at peripheral muscarinic sites and their effects on central nervous system-mediated symptoms and signs may not be clinically significant. 

The lost sites are most likely presynaptic nicotinic sites. These facts may lead to a more rational therapeutic approach. 

The reactivation of AChE allows ACh to be hydrolyzed in the normal way, and therefore normal cholinergic neuro-transmission will resume. It is usually considered that the beneficial effects of oximes in OP poi.soning arc confined to peripheral nicotinic sites and that CNS effects are clinically insignificant (Bismuth etaL, 1992), although there is evidence that PAM can cross the blood-brain barrier (Sakurada etaL, 2003). This means that the beneficial effects will mainly be on neuromuscular transmission, and that there will be little action on parasympathetic effects, such as bronchoirhea, bronchoconstriction, and rhinorrhea, or on CNS effects. 

When atropine was administered in adequate amounts before the failure of circulation, it reversed the central depression and bronchoconstriction but not the neuromuscular block, a finding that might be expected, because the neuromuscular effects of poisoning with these nerve agents occur at a nicotinic site.64,68... 

Whereas the radius of every inorganic ion, in the anhydrous state, is well established, those of low mass are strongly hydrated in solution so that their effective radius is much greater. Just how much greater cannot be said because an exact method for measurement is lacking. However, the figures for Li and Na" " in the last column of Table 12.2 are indicative. The cationic head is the widest part of the acetylcholine molecule. What happens if it is made wider First, let us note the acetylcholine-like effect of simple aliphatic quaternary amines. These have only a feeble action on muscarinic sites, although their action on nicotinic sites is considerable (see below). Tetramethylammonium salts, for example, have only about one-thousandth of the activity of acetyl-... 

Toxic action of AChE inhlntors. Withcxjt AChE, ACh accumulates and causes excessive synaptic neurotransmitter activity in the parasympathetic (cholinergic) nervous system and at neuromuscular (nicotinic) sites. 

Antidotes. Because the acute toxicity to man of many of the phosphorus insecticides is high, first-aid remedies are kept on hand. The most useful of these is an injection of atropine (which acts primarily on muscarinic sites) followed by an oxime specific for nicotinic sites. These oximes reactivate phosphorylated acetylcholinesterase in patients (Holmes and Robins, 1955) just as with the isolated enzyme (Wilson and Meislich, 1953). This reaction involves a competition, between the hydroxyl-groups of serine and of the hydroxylamine, for the phsphoryl-group. The covalent bond with the serine is broken, and simultaneously a new covalent bond formed with the hydroxylamine (see Scheme 12.1). One of the best reactivators is pralidoxime 12.27) (2-PAM), which is the anti form of pyridine-2-aldoxime methochloride. Widely differing doses of antidote are required, depending on the strength of the phosphate-enzyme bond, which varies with the nature of the insecticide. 

The optimal position for an oxygen atom in the side-chain. The ether ( 3-59) has approximately i to lo per cent of the activity of acetylcholine, and is more active at muscarinic than at nicotinic sites. This activity is diminished if the oxygen atom is moved from the 3- to the 2- or 4-position. The ketone (13.61) has little muscarinic (but from 0.2 to too per cent of the nicotinic) action of acetylcholine on various test preparations. If the carbonyl-group is moved from the 4- to the 3- or 2-position, the action is diminished (Ing, Kordik, and Williams, 1952). Thus both the ethereal and carbonyl oxygen atoms have maximal activity in the positions where they occur in acetylcholine (13.44). 

Tetramethylammonium salts and acetylcholine salts are equipotent at autonomic ganglia sites (Burn and Dale, 1915), but the former have only one-hundreth of this potency at the skeletal neuromuscular junaion which is also a nicotinic site, and only one-thousandth at smooth muscle jimctions (muscarinic). Only transient demands are made on the transmitter at autonomic ganglia, whereas a nerve-muscle junction requires a lingering action greatly facilitated by molecules that permit hydrogen-bonding as in acetylcholine. Apparently the tetramethylammonium cation is the... 

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