Toxics Action Center

These agents reduce sympathetic outflow from vasomotor centers in the brain stem but allow these centers to retain or even increase their sensitivity to baroreceptor control. Accordingly, the anti hypertensive and toxic actions of these drugs are generally less dependent on posture than are the effects of drugs that act directly on peripheral sympathetic neurons. 

The fasciculins are a family of closely related peptides that are isolated from the venom of mambas and exert their toxic action by inhibiting AChE. The crystal structure of fasciculin 2 from green mamba Dendroaspis angusticeps) snake venom was first resolved in 1992 (Le Du et al., 1992). The three-dimensional (3D) structure of fasciculin 1 obtained from the US National Library of Medicine, National Center for Biotechnology Information, MMDB database is illustrated in Figure 11.2. 

Although the crystal structure of CODH or CODH/ACS has not yet been solved, a great deal of work has been done on these enzymes and plausible catalytic mechanisms have been proposed. Concerted action between the Ni ion and one of the Fe centers of a 4Fe-4S cluster are thought to elicit the formation of CO2 from CO. But perhaps the most extraordinary reaction is the one catalyzed by Cluster A the insertion of CO to a Ni-CHs complex. Through the two reactions catalyzed by CODH/ACS, the highly toxic, CO is not only removed, but is used as a source of carbon and electrons. 

Dioxin-contaminated sites, which pose a human health threat, have been the subject of recent analyses by the Centers for Disease Control (CDC) in Atlanta, GA. It has been determined by CDC that 1 ppb of dioxin is detrimental to public health and that people should be dissociated from the hazard. A level of 1 ppb of dioxin (2,3,7,8-TCDD) in soil is recommended as an action level. In cases where soil concentrations exceed 1 ppb, it is recommended by CDC that potential human exposure to the contamination be examined further. If there is human exposure to I ppb or higher on a regular basis, cleanup is indicated. A substance that may be more toxic and hazardous than dioxin is expected to be discovered in the near future. 

Low doses of nicotine stimulate respiration through activation of chemoreceptors in the aortic arch and carotid bodies, while high doses directly stimulate the respiratory centers. In toxic doses, nicotine depresses respiration by inhibiting the respiratory centers in the brainstem and by a complex action at the receptors at the neuromuscular junction of the respiratory muscles. At these neuromuscular receptors, nicotine appears to occupy the receptors, and the end plate is depolarized. After this, the muscle accommodates and relaxes. These central and peripheral effects paralyze the respiratory muscles. 

At doses up to those causing hypnosis, no significant effects on the cardiovascular system are observed in healthy patients. However, in hypovolemic states, heart failure, and other diseases that impair cardiovascular function, normal doses of sedative-hypnotics may cause cardiovascular depression, probably as a result of actions on the medullary vasomotor centers. At toxic doses, myocardial contractility and vascular tone may both be depressed by central and peripheral effects, leading to circulatory collapse. Respiratory and cardiovascular effects are more marked when sedative-hypnotics are given intravenously. 

The induction of unconsciousness may be the result of exposure to excessive concentrations of toxic solvents such as carbon tetrachloride or vinyl chloride, as occasionally occurs in industrial situations (solvent narcosis). Also, volatile and nonvolatile anesthetic drugs such as halothane and thiopental, respectively, cause the same physiological effect. The mechanism(s) underlying anesthesia is not fully understood, although various theories have been proposed. Many of these have centered on the correlation between certain physicochemical properties and anesthetic potency. Thus, the oil/water partition coefficient, the ability to reduce surface tension, and the ability to induce the formation of clathrate compounds with water are all correlated with anesthetic potency. It seems that each of these characteristics are all connected to hydrophobicity, and so the site of action may be a hydrophobic region in a membrane or protein. Thus, again, physicochemical properties determine biological activity. 

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