Cardiac sensitisation

Hardy, C.J., I.I.Sharman, and G.C.Clark. 1991. Assessment of cardiac sensitisation potential in dogs comparison of HFA 134a and A12. Report No. CTL/C/2521. Huntingdon Research Centre, Huntingdon, Cambridgeshire. 

Hardy, C.J., P.C.Kieran, and I.I.Sharman. 1994. Assessment of the cardiac sensitisation potential (CSP) of a range of halogenated alkanes. Toxicologist 14 378. 

Hardy, J.C., I.J.Sharman, and D.O.Chanter. 1989a. Assessment of cardiac sensitisation potential in dogs and monkeys. Comparison of I-141b and FI 1. PWT 86/89437, Huntingdon Research Centre Ltd., Huntingdon, Cambridgeshire, England. 

Mullin, L.S. 1977. Cardiac sensitisation. Haskell Laboratory Report 957—77, E.I. duPont de Nemours and Co., Newark, DE. 

In addition, many solvents have been shown to cause cardiac sensitisation at very high exposure levels and this may also be regarded as an effect related to the solvent properties of the molecule. 

Cardiac sensitisation. Many solvents, at very high exposure levels, are able to affect the heart such that it becomes particularly sensitive to the effects of adrenaline or similar agents, whether generated internally within the body or administered therapeutically. This is known as cardiac sensitisation. In extreme cases, adrenaline generated by exercise or sudden shock can cause the sensitised heart suddenly to cease functioning. This is one of the hazards specifically associated with solvent abuse. 

CNS effects will occur. Cardiac sensitisation only occurs at very high concentrations (which for most solvents approach or exceed anaesthetic levels) and is thus unlikely to be of significance in normal industrial practice. 

Tetrachloroethylene. Tetrachloroethylene (OES 50 ppm 8h TWA) is broadly similar to trichloroethylene in its toxicological profile. Mild adverse liver and kidney effects have been reported in humans who have been overexposed and tumours have been seen in animals exposed over their lifetime. Tetrachloroethylene follows similar metabolic pathways to trichloroethylene, and similar arguments to those developed for trichloroethylene cast doubt on the relevance of these tumours for humans. Mild CNS disturbances and eye irritation are considered to be the critical health effects in humans. Cardiac sensitisation has not been reported in animal studies, unusual among the halogenated solvents. 

Trichloroethane 1,1,1-Trichloroethane (OES 200ppm 8h TWA) is one of the least toxic members of this group, probably due to the small extent to which it is metabolised. Very little effect is seen on the liver in animal experiments and lifetime studies have shown no carcinogenic effect. Extremely high exposures may lead to cardiac sensitisation and there have been reports of sudden deaths, some of which have been associated with solvent abuse. This solvent is being phased out under the Montreal Protocol. 

Trichloro-1,2,2- trifluoroethane. 1,1,2-T richloro-1,2,2-trifluoroethane or fluorocarbon-113 (OES 1000 ppm 8h TWA) is possibly the least toxic of the solvents that have been in common use within this group. Apart from CNS effects and the ability to cause cardiac sensitisation at very high exposure levels, this solvent has been shown to cause few adverse effects. This absence of systemic toxicity is attributable to a rapid rate of elimination from the body and a very low degree of metabolism. This solvent is being phased out of production under the Montreal Protocol. 

In contrast to halothane, cardiac arrhythmias are uncommon with isoflurane and it does not sensitise the heart to the effects of catecholamines. 

Sevoflurane, in common with all volatile agents, reduces cardiac output and systemic blood pressure. It does so mainly through a reduction in peripheral vascular resistance. Although it is a systemic vasodilator it does not appear to produce significant dilatation of small coronary vessels and there is no possibility of coronary steal as hypothesised for isoflurane. A small increase in heart rate may be observed. This is less pronounced than with isoflurane and desflurane and is almost certainly the result of reflex activity secondary to the reduction in peripheral vascular resistance. Sevoflurane is associated with a stable heart rhythm and does not predispose the heart to sensitisation by catecholamines. In children, halothane causes a greater decrease in heart rate, myocardial contractility and cardiac output than sevoflurane at all concentrations. For these reasons sevoflurane is advocated for use in outpatient dental anaesthesia, especially in children. 

Enflurane produces a dose-related decrease in systemic arterial blood pressure secondary to reductions in cardiac output and systemic vascular resistance. There is evidence that cardiac output is partially maintained by a compensatory increase in heart rate. This effect seems dependent on a degree of hypercardia and does not occur during controlled ventilation. Enflurane and halothane depress myocardial contractility to a similar extent and less than isoflurane. Enflurane does not sensitise the heart to the effects of catecholamines to any significant extent and adrenaline (epinephrine) may be given subcutaneously for control of bleeding. 

Digoxin remains the mainstay of treatment for patients with chronic myocardial failure. Other drugs with inotropic and/or vasodilator properties, including the catecholamines and phosphodiesterase III (PDE) inhibitors, are used in the treatment of acute cardiac failure. The inotropic actions of most of these drugs result from a direct or indirect elevation of [Ca2-i-]i (intracellular Ca2+ concentration). This acts as a trigger for a process which leads to increased contractile state and cardiac contraction (Figures 8.3 and 8.4). Myofilament calcium sensitisers increase the sensitivity of contractile proteins to calcium. Some newer drugs, such as vesnarinone, have multiple mechanisms of action. 

Volatile solvent abuse or glue sniffing, is common among teenagers, especially males. The success of the modem chemical industry provides easy access to these substances as adhesives, dry cleaners, air fresheners, deodorants, aerosols and other products. Various techniques of administration are employed viscous products may be inhaled from a plastic bag, liquids from a handkerchief or plastic bottle. The immediate euphoriant and excitatory effects are replaced by confusion, hallucinations and delusions as the dose is increased. Chronic abusers, notably of toluene, develop peripheral neuropathy, cerebellar disease and dementia damage to the kidney, liver, heart and limgs also occurs with solvents. Over 50% of deaths from the practice follow cardiac arrhythmia, probably caused by sensitisation of the myocardium to catecholamines and by vagal inhibition... 

Halothane has the highest blood/gas partition coefficient of the volatile anaesthetic agents and recovery from halothane anaesthesia is comparatively slow. It is pleasant to breathe and is second choice to sevoflurane for inhalational induction of anaesthesia. Halothane reduces cardiac output more than any of the other volatile anaesthetics. It sensitises the heart to the arrhythmic effects of catecholamines and hypercapnia arrhythmias are common, in particular atrioventricular dissociation, nodal rhythm and ventricular extrasystoles. Halothane can trigger malignant hyperthermia in those who are genetically predisposed (see p. 363). 

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