Catecholamines toxicity

Graham, D.G. (1984). Catecholamines toxicity a proposal for the molecular pathogenesis of manganese toxicity and Parkinson s disease. Neurotoxicolc 5, 83-96. 

At pH 6.36, however, the cyclization products appear as a new redox couple that corresponds to the respective dihydroindole product. This process is of particular biological significance since the rate of cyclization of the oxidized form of catecholamines is a major factor in determination of catecholamine toxicity. Such toxicity results from competitive reactions of the oxidized quinonoid form of the catecholamines with sulfhydryl groups of some essential enzymes. Thus, the fast cyclizing TV-methylsubstituted catecholamines are less toxic than the unsubstituted ones that cyclize more slowly. Moreover, 1/2 potentials (rotating carbon electrode) of catecholamines were successfully correlated with their cytotoxicity (279), justifying the importance of the electron-transfer step. 

Graham DG. Catecholamine toxicity a proposal for the molecular pathogenesis of... 

Sanchez-Recalde A, Iborra C, Costero O, Moreno R, Lopez de Sa E, Sobrlno JA, Lopez-Sendon JL. Isolated left ventricular basal ballooning in young women inverted takotsubo pattern related to catecholamine-toxicity. Am J Cardiol 2007 100(9) 1496-7. 

Halogenated hydrocarbons depress cardiac contractility, decrease heart rate, and inhibit conductivity in the cardiac conducting system. The cardiac-toxicity of these compounds is related to the number of halogen atoms it increases first as the number of halogen atoms increases, but decreases after achieving the maximum toxicity when four halogen atoms are present. Some of these compounds, e.g., chloroform, carbon tetrachloride, and trichloroethylene, sensitize the heart to catecholamines (adrenaline and noradrenaline) and thus increase the risk of cardiac arrhythmia. 

It is generally aeeepted that COMT is an extraeellular enzyme in the CNS that catalyses the transfer of methyl groups from S-adenylmethionine to the meta-hydroxy group of the eateehol nueleus. Until recently the only inhibitors of this enzyme were pyragallol and eateehol whieh were too toxic for clinical use. Now other inhibitors have been developed, e.g. entaeapone and tolcapone, but these are used mainly to protect dopa (also a catecholamine) from O-methylation, in the treatment of Parkinson s disease (Chapter 15). 

Effects in Laboratory Animals. As highlighted in other chapters, the central toxicities during and after repeated stimulant bingeing may be related to neuronal or terminal destruction and/or depletion of neurotransmitter in the brain. In monkeys and cats, the report by Duarte-Escalante and Ellinwood (1970) of neuronal chromatolysis associated with decreased catecholamine histofluorescence following chronic METH intoxication has been followed by extensive neurochemical demonstrations of damage to the monoamine pathways by chronic stimulants (Seiden and Ricaurte 1987). 

Copper is part of several essential enzymes including tyrosinase (melanin production), dopamine beta-hydroxylase (catecholamine production), copper-zinc superoxide dismutase (free radical detoxification), and cytochrome oxidase and ceruloplasmin (iron conversion) (Aaseth and Norseth 1986). All terrestrial animals contain copper as a constituent of cytochrome c oxidase, monophenol oxidase, plasma monoamine oxidase, and copper protein complexes (Schroeder et al. 1966). Excess copper causes a variety of toxic effects, including altered permeability of cellular membranes. The primary target for free cupric ions in the cellular membranes are thiol groups that reduce cupric (Cu+2) to cuprous (Cu+1) upon simultaneous oxidation to disulfides in the membrane. Cuprous ions are reoxidized to Cu+2 in the presence of molecular oxygen molecular oxygen is thereby converted to the toxic superoxide radical O2, which induces lipoperoxidation (Aaseth and Norseth 1986). 

In all tested organisms, PCBs — especially PCBs with 2,3,7,8-TCDD-like activity — adversely affected patterns of survival, reproduction, growth, metabolism, and accumulation. Common manifestations of PCB exposure in animals include hepatotoxicity (hepatomegaly, necrosis), immunotox-icity (atrophy of lymphoid tissues, suppressed antibody responses), neurotoxicity (impaired behavior and development, catecholamine alterations), increased abortion, low birth weight, embryolethality, teratogenicity, gastrointestinal ulceration and necrosis, bronchitis, dermal toxicity (chloracne, edema,... 

Kanthasamy AG, Borowitz JL, Isom GE. 1991b. Cyanide-induced increases in plasma catecholamines Relationship to acute toxicity. Neurotoxicology 12 777-784. 

Although some steroids have been reported to reduce the toxic effects of some insecticides, the steroid ethylestrenol decreased the rate of recovery of depressed cholinesterase activity in disulfoton- pretreated rats (Robinson et al. 1978). The exact mechanism of this interaction was not determined. Ethylestrenol alone caused a small decrease in cholinesterase activity, and, therefore, resulted in an additive effect. Rats excreted less adrenaline and more noradrenaline when given simultaneous treatments of atropine and disulfoton compared with rats given disulfoton alone (Brzezinski 1973). The mechanism of action of disulfoton on catecholamine levels may depend on acetylcholine accumulation. In the presence of atropine, the acetylcholine effect on these receptors increases the ability of atropine to liberate catecholamines. 

Peroxynitrite (ONOO ) is a cytoxic species that is considered to form nitric oxide (NO) and superoxide (Oj ) in biological systems (Beckman et al. 1990). The toxicity of this compound is attributed to its ability to oxidize, nitrate, and hydroxylate biomolecules. Tyrosine is nitrated to form 3-nitrotyrosine (Ramazanian et al. 1996). Phenylalanine is hydroxylated to yield o-, m-, and p-tyrosines. Cysteine is oxidized to give cystine (Radi et al. 1991a). Glutathione is converted to S-nitro- or S-nitroso derivatives (Balazy et al. 1998). Catecholamines are oxidatively polymerized to melanin (Daveu et al. 1997). Lipids are also oxidized (Radi 1991b) and DNA can be scissored by peroxynitrite (Szabo and Ohshima 1997). 

Toxicology. Trichlorofluoromethane is toxic by several mechanisms It can sensitize the myocardium to catecholamines, resulting in ventricular arrhythmias it can have an anesthetic effect on the central nervous system... 

Cardiovascular Effects. Inhalation and oral studies in humans and animals have not revealed any treatment-related histopathological lesions of heart tissue, or impairment of cardiac functions, even at dose levels causing severe liver and kidney damage (Adams et al. 1952 Stewart et al. 1961 Umiker and Pearce 1953). It is possible that high-level carbon tetrachloride exposure may produce cardiac arrhythmias by sensitization of the heart to catecholamines (Reinhardt et al. 1971). Accordingly, there is some concern for cardiovascular toxicity following substantial exposure to carbon tetrachloride. 

Due to the widespread physiological functions, catecholamines can be used clinically for numerous indications. However, specific effects are most commonly associated with unwanted effects. Catecholamines are very potent drugs - 1 mg is a toxic dose - although the interindividual sensitivity can vary considerably. 

Isoflurane, an isomer of enflurane, together with sevoflurane are the most commonly used inhalation anesthetics in humans. Isoflurane does not sensitize the myocardium to catecholamines, has muscle relaxing action so less neuromuscular blocker is required and causes less hepatotoxicity and renal toxicity than halothane. 

The drug disulfiram interferes with the oxidation of acetaldehyde formed during the metabolism of alcohol. This increases the blood level of acetaldehyde which acts directly on cardiovascular system and produce these toxic reactions. Disulfiram also inhibits dopamine beta oxidase and thus interferes with the synthesis of noradrenaline, which causes depletion of catecholamines. 

Phenoxybenzamine Irreversibly blocks a and Lowers blood pressure (BP) but heart rate (HR) rises due to baroreflex activation Pheochromocytoma high catecholamine states Irreversible blocker half-life > 1 day Toxicity Orthostatic hypotension tachycardia myocardial ischemia... 

Many factors can precipitate or exacerbate arrhythmias ischemia, hypoxia, acidosis or alkalosis, electrolyte abnormalities, excessive catecholamine exposure, autonomic influences, drug toxicity (eg, digitalis or antiarrhythmic drugs), overstretching of cardiac fibers, and the presence of scarred or otherwise diseased tissue. However, all arrhythmias result from (1) disturbances in impulse formation, (2) disturbances in impulse conduction, or (3) both. 

Bupropion Increased norepinephrine and dopamine activity Presynaptic release of catecholamines Major depression smoking cessation (bupropion) sedation Extensive metabolism in liver Toxicity Lowers seizure threshold (amoxapine,... 

Hydroxy dopamine is a selectively neuro toxic compound, which damages the sympathetic nerve endings. It can be seen from Figure 7.43 that 6-hydroxydopamine is structurally very similar to dopamine and noradrenaline, and because of this similarity it is actively taken up into the synaptic system along with other catecholamines. Once localized in the synapse, the 6-hydroxydopamine destroys the nerve terminal. A single small dose of 6-hydroxydopamine destroys all the nerve terminals and possibly the nerve cells as well. 

Factors that influence the disposition of catecholamines will affect the toxicity. For instance, compounds that inhibit the uptake of noradrenaline reduce the destruction of adrenergic nerve terminals but not of dopaminergic ones. Interference with the oxidative metabolism of catecholamines also influences the toxicity of 6-hydroxydopamine. 

Cocaine, which blocks the uptake of catecholamines, produces dose-dependent effects, initially causing euphoria, vasoconstriction, and tachycardia, and in toxic doses, convulsions, myocardial depression, ventricular fibrillation, medullary depression, and death. Cocaine is able to block nerve conduction and currently is used only for topical anesthesia. 

Pemoline, an oxizolidine compound, acts similarly to methylphenidate—through catecholamine uptake inhibition in the CNS (27) with minimal sympathomimetic effects (57). Although pemoline is not the first-line stimulant for the treatment of ADHD, it has been successfully used for the treatment of this disorder in both children and adults (28,30). Pemoline has also been used for the treatment of daytime sleepiness associated with narcolepsy (31), and although it is somewhat effective for this purpose (33), it is not a first-line choice owing to its potentially lethal liver toxicity. 

Central nervous system toxicity is rarely observed with catecholamines or drugs such as phenylephrine. In moderate doses, amphetamines commonly cause restlessness, tremor, insomnia, and anxiety in high doses, a paranoid state may be induced. Cocaine may precipitate convulsions, cerebral hemorrhage, arrhythmias, or myocardial infarction. Therapy is discussed in Chapter 59 Management of the Poisoned Patient. 

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