Effects and toxicity

Neuromuscular blockers can be analyzed using HPLC with fluorescence, ultraviolet (UV), or electrochemical detection (ECD). As an alternative to HPLC, GC with nitrogen—phosphorus detection (NPD) and LC coupled with electrospray ionization tandem mass spectrometry (ESI-MS-MS) have also been investigated as viable techniques to measure neuromuscular blockers (Table 10.2). 

Regardless of the chromatographic technique, NMBAs are purified from biological tissues and fluids by both liquid-liquid extractions (LLE) and solid-phase extractions (SPE). Because many NMBAs have a short half-life (e.g. suxamethonium, ti/, 0.7 min). 

Mechanism of toxicity Non-depolarizing NMBAs Depolarizing NMBAs 

Skeletal muscle blockade Prolonged apnea ( 20 s) Prolonged apnea 

Signal measured analyte peak height relative to concentration Run Time Not Reported Pretreatment  

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Side Effects and Toxicity. Adverse effects to the tricycHc antidepressants, primarily the result of the actions of these compounds on either the autonomic, cardiovascular, or central nervous systems, are summarized in Table 3. The most serious side effects of the tricycHcs concern the cardiovascular system. Arrhythmias, which are dose-dependent and rarely occur at therapeutic plasma levels, can be life-threatening. In order to prevent adverse effects, as weU as to be certain that the patient has taken enough dmg to be effective, the steady-state semm levels of tricycHc antidepressant dmgs are monitored as a matter of good practice. A comprehensive review of stmcture—activity relationships among the tricycHc antidepressants is available (42). 

The Class I agents have many similar side effects and toxicities. The anticholinergic side effects include dry mouth, constipation, and urinary hesitancy and retention. Common gastrointestinal (GI) side effects include nausea, vomiting, diarrhea, and anorexia. Cardiovascular adverse effects are hypotension, tachycardia, arrhythmias, and myocardial depression, especially in patients with congestive heart failure. Common central nervous system (CNS) side effects are headache, dizziness, mental confusion, hallucinations, CNS stimulation, paraesthesias, and convulsions. 

The side effects and toxic reactions to verapamil iaclude upper GI upset, constipation, di22iaess, headaches, flushing and burning, edema, hypotension, bradycardia, and various conduction disturbances. Verapamil has negative iaotropic activity and may precipitate heart failure ia patients having ventricular dysfunction (1,2). 

Disulfiram is usually given orally. Because there is an increased risk of side effects and toxic hazards as the dosage is increased, the daily dosage prescribed in the United States has been limited to 250—500 mg/day. However, efforts to titrate the dosage of disulfiram in relation to a challenge dose of ethanol indicated that some patients require in excess of 1 g/day of disulfiram to reach blood levels sufficient to produce a DER (Brewer 1984). 

Fenwick, G. R. 1988. Bracken (Pteridium aquilinum). Toxic effects and toxic constituents. J. Sci. Pood Agile. 46 147-173. 

The priority effects are carcinogenicity, mutagenicity, reproductive or developmental toxicity, endocrine disruption and neurotoxicity. Human toxicity is broader than priority effects, including acute toxicity, systemic toxicity (organ effects), immune system effects and skin/eye/respiratory damageaswellasthepriority effects. And toxicity as T includes both human toxicity and ecotoxicity. 

OWENS has prepared antibodies to PCP in goats. When administered to mice the PCP levels in blood rose tenfold as an antibody-bound form that was readily excreted in urine. BROWNE tested the selfadministration by rats of 1,000 compounds related (and not related) to PCP, some of which produced PCP-like effects. One compound that was self-administered prevented the entrance of PCP into brain. BALSTER gave a general review of the effects produced by PCP in laboratory animals and showed that some effects were similar to those produced by amphetamine, some to barbiturates, and some to antipsychotics. This response profile makes PCP a unique drug that stands alone in its complex effects and toxicity. 

Mehlman MA. 1994. Dangerous and cancer-causing properties of products and chemicals in the oil refining and petrochemical industry. Part VII Adverse health effects and toxic manifestations caused by exposure to hydrogen sulfide, a component of crude oil. Advances in Modem Environmental Toxicology 23 321-340. 

Alles, G.A. The comparative physiological actions of the DL-beta-phenylisopropylamines. I. Pressor effect and toxicity. J. Pharmacol. Exp. Ther. 47 339, 1933. 

Quan, Y. S., Hattori, K., Lundborg, E., Fujita, T., Murakami, M., Muranishi, S., Yamamoto, A., Effectiveness and toxicity screening of various absorption enhancers using Caco-2 cell monolayers, Biol. Pharm. Bull. 1998, 21, 615-620. 

Yamane T, Nakatani H, Kikuoka N, and others. 1996. Inhibitory effects and toxicity of green tea polyphenols for gastrointestinal carcinogenesis. Cancer 77(8 Suppl) 1662-1667. 

Environmentally safe destruction of obsolete chemical weapons must be performed In facilities which assure total containment of blast effects and toxic gas In the event of an accidental detonation. Functional process requirements and recommended structural design procedures for containment rooms to accomplish this purpose are presented. The requirements presented are consistent with Department of the Army and Department of Defense Explosive Safety Board requirements. 

Developed as an animal tranquilizer by Parke-Davis Co., a pharmaceutical firm in Detroit, it is now manufactured legally only by Bio-Ceutics, a firm in St. Joseph, Missouri. The drug is not prescribed for human beings because the range between effective and toxic doses is narrow. 

Discussion. From the investigations of the compounds described so far, it is evident that the myotic effect and toxicity of the molecule POX(0 CH-fti2 )2 depend upon the nature of X, B and B. In this particular type2 of molecule if X is fluorine, then high toxicity and myotic properties result. Myotic effect is absent and toxicity is of a low order if X = H, Et,... 

In the molecule (X = F), the pupil-constricting action and toxicity are increased by a secondary grouping (e.g. R=R = Me . R = Me, 72 = Et RR = cycZohexyl R = Me, R = CH2 CHMe2). Furthermore, it appears that for non-cyclic compounds both R and R, for the best results, must be unsubstituted hydrocarbon radicals (e.g. if R = Me and R = C02Et the compound is scarcely toxic). Similarly, if R =. S = CH2C1, both the myotic effect and toxicity are of a low order. Among unsubstituted (non-cyclic) secondary radicals, the best results seem to be obtained when one group, at least, is Me for example, if. R =. R = Et, the toxicity is considerably reduced. 

It is not practical here, of course, to attempt to list all the chemicals that can be found in the workplace, far less to describe their effects and toxicity. The list, of course, will vary according to the nature of the work. The chemicals found in paint manufacturing, for instance, will be different from those occurring in a foundry. The nature and occurrence of some of the more common of these industrial chemicals, along with their toxic effects, is examined in Chapter 7. 

S. B. A. Akerman, S. B. Ross, A. Tele, The Enzymatic Hydroysis of a Series of Ami-noacylanibdes in Relation to Their Nerve Blocking Effect and Toxicity , Acta Pharmacol. Toxicol. 1973, 32, 88-96. 

A., Effectiveness and toxicity screening of various absorption enhancers using Caco-2 cell monolayers., Biol. Pharm. Bull., 21, 620,1998. 

Many CNS depressants have some liability for dependence. This is typically greater with barbiturates, but lesser with benzodiazepines, and perhaps nonexistent in many antiseizure medications. CNS depressants produce tolerance when administered chronically, where increasingly larger doses are required to sustain the same level of effect. Further, a cross-tolerance often develops, where the tolerance is generalized to other CNS depressants. For example, a person with an ethanol tolerance will also display some tolerance to barbiturates. The therapeutic index tends to decrease as tolerance increases, so that the difference between an effective and toxic dose diminishes. Thus, tolerance to CNS depressants is accompanied by a smaller safety margin. 

Maluf E, Baros HMT, Frochtengarten ML, Benti R, Leite JR. (1991). Assessment of the hypnotic/sedative effects and toxicity of Passiflora edulis aqueous extract in rodents and humans. Phytother Res. 5(6) 262-66. 

The traditional scheme is complicated by the fact that some antidepressants exhibit characteristics of more than one class. For example, clomipramine, a tricyclic antidepressant (TCA) with side effects and toxicity similar to other TCAs, works more like the selective serotonin reuptake inhibitors (SSRls). Similarly, venlafaxine and duloxetine, which are usually grouped with the atypical antidepressants, have a side effect and safety profile comparable to the SSRls. Although a classihcation system based on mechanism of action offers some advantage (see Table 3.7), even this scheme is limited by the fact that antidepressants that work in the same way may have widely divergent side effect and safety profiles. In the following discussion, the traditional classification system is adopted. Although fraught with problems and inconsistencies. 

Venlafaxine (Effexor, Effexor XR). Venlafaxine works by blocking the reuptake of both serotonin and norepinephrine. Because of this dual action, some believe that venlafaxine may be more effective than the SSRIs when treating severe depression. Its side effects and toxicity are similar to the SSRIs with abdominal discomfort, sexual dysfunction, and anxiety being commonly reported. At higher doses, it may mildly elevate blood pressure therefore, blood pressure should be checked periodically. When stopping venlafaxine, serotonin discontinuation symptoms may be especially problematic. Therefore, gradually tapering of the dose every 2-4 weeks is recommended. 

Specific Serotonin Reuptake inhibitors (SSRis). To date, the only SSRI studied in AN is fluoxetine (Prozac). During the acute refeeding phase of treatment, fluoxetine shows modest improvement in weight gain while a larger controlled study during the maintenance phase of treatment demonstrated effectiveness in the prevention of relapse. From the standpoint of side effects and toxicity, the SSRIs are clearly... 

In psychopharmacology, interest in the properties of enantiomers has been aided by the need to improve the therapeutic efficacy and decrease the side effects and toxicity of drugs. For example, if the therapeutic activity resides entirely in one enantiomer (called a eutomer) then giving a racemic mixture which contains the active and the inactive enantiomer is clearly wasteful. Thus using the single enantiomer (isomer or eutomer) should enable the dose of the drug to be lowered, reduce the interpatient variability in the response and, hopefully, reduce the side effects and toxicity of the drug (see Table 3.4). 

The discovery of medicinal alkaloids from Catharanthus roseus G. Don (Vinca rosea L.) represents one of the most important introductions of plant products into the cancer chemotherapeutic armamentarium. The relatively unique effects and toxicities of these agents have allowed the design of multiagent chemotherapy programs that have demonstrated sufficient effectiveness to achieve cures even of advanced tumors in many instances. This great accomplishment is possible only because of the inclusion of many different drugs, including the binary Vinca alkaloids. 

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