Epinephrine toxicity

Lidocaine Blockade of sodium channels Slows, then blocks action potential propagation Short-duration procedures epidural, spinal anesthesia Parenteral duration 30-60 min 2-6 h with epinephrine Toxicity CNS excitation... 

Procaine Like lidocaine Like lidocaine Very short procedures Parenteral duration 15-30 min 30-90 min with epinephrine Toxicity Like lidocaine... 

Detoxifica.tlon. Detoxification systems in the human body often involve reactions that utilize sulfur-containing compounds. For example, reactions in which sulfate esters of potentially toxic compounds are formed, rendering these less toxic or nontoxic, are common as are acetylation reactions involving acetyl—SCoA (45). Another important compound is. Vadenosylmethionine [29908-03-0] (SAM), the active form of methionine. SAM acts as a methylating agent, eg, in detoxification reactions such as the methylation of pyridine derivatives, and in the formation of choline (qv), creatine [60-27-5] carnitine [461-06-3] and epinephrine [329-65-7] (50). 

Isoflurane is a respiratory depressant (71). At concentrations which are associated with surgical levels of anesthesia, there is Htde or no depression of myocardial function. In experimental animals, isoflurane is the safest of the oral clinical agents (72). Cardiac output is maintained despite a decrease in stroke volume. This is usually because of an increase in heart rate. The decrease in blood pressure can be used to produce "deHberate hypotension" necessary for some intracranial procedures (73). This agent produces less sensitization of the human heart to epinephrine relative to the other inhaled anesthetics. Isoflurane potentiates the action of neuromuscular blockers and when used alone can produce sufficient muscle relaxation (74). Of all the inhaled agents currently in use, isoflurane is metabolized to the least extent (75). Unlike halothane, isoflurane does not appear to produce Hver injury and unlike methoxyflurane, isoflurane is not associated with renal toxicity. 

Lidocaine hydrochloride [73-78-9] (Xylocaine), is the most versatile local anesthetic agent because of its moderate potency and duration of action, rapid onset, topical activity, and low toxicity. Its main indications are for infiltration, peripheral nerve blocks, extradural anesthesia, and in spinal anesthesia where a duration of 30 to 60 min is desirable. Because of its vasodilator activity, addition of the vasoconstrictor, epinephrine, increases the duration of action of Hdocaine markedly. It is also available in ointment or aerosol preparations for a variety of topical appHcations. 

The COMT inhibitors should not be administered with the monoamine oxidase (MAO) inhibitors (see Chap. 31) because there is an increased risk of toxicity. If the COMT inhibitors are administered with norepinephrine, dopamine, dobutamine, methyldopa, or epinephrine, there is a risk of increased heart rate, arrhythmias, and excessive blood pressure changes. 

Chlorpromazine (CPZ) and pentoxifylline (PTX) were shown to inhibit TNF release and improve survival during murine endotoxemia (Gl). CPZ (M25) and epinephrine (PI6) pretreatment markedly up-regulated IL-10 production induced by LPS, a phenomenon also observed with cyclosporine (Dl). PTX pretreatment did not affect LPS-induced IL-10 release. Thus, TNF and IL-10 can be differentially regulated during murine endotoxemia. The sustained or even increased production of IL-10 could play a role in the protective effects of these drugs against LPS toxicity in vivo. 

Chengelis, C.P. 1997. Epinephrine sensitivity of the canine heart A useful test. In R.Snyder, K.S.Bakshi, and B.M.Wagner, Abstracts of the Workshop on Toxicity of Alternatives to Chlorofluorocarbons. Inhal. Toxicol. 9 775—810. 

Humans exposed at high concentrations of some halogenated hydrocarbons can develop cardiac arrhythmias. The cardiac sensitization test in dogs is considered an effective determination of potential cardiac sensitization in humans. Cardiotoxicity was observed at concentrations well below those associated with any acute toxic signs but only in the presence of greater-than-physiological doses of exogenous epinephrine. 

In rats, 90 day exposures to 1000 and 5000 ppm caused bilateral hair loss, extensive liver damage, and excessive mortality. The chronic toxicity of dichlorofluoromethane appears to be quite different from difluorinated methanes and more similar to the hepatotoxin chloroform. In mice 100,000 ppm induced arrhythmias and sensitized the heart to epinephrine. 

The mechanism of antidepressive action of this series of drugs is likely associated with their inhibition of the oxidizing deamination process of the neurotransmitters norepinephrine, epinephrine, dopamine, and serotonin, which participate in the transmission of nerve excitement in the CNS. A major drawback of these drugs is the high toxicity associated with their inhibition of not only MAO, but also a number of other nonspecific enzymes. 

Ephedrine is an alkaloid that is present in various forms of the ephedrine family, and which is still extracted from Ephedra sinica and Ephedra equisetina. Because of the presence of two asymmetric atoms, there are four isomeric forms. Pseudoepinephrine (d-isoephrine) is a stereoisomer with pharmacological action that differs slightly from ephedrine. The pharmacological action of ephedrine is typical of noncatecholamine sympathomimetics of mixed action. It stimulates both a- and 8-adrenoreceptors, and simultaneously causes a release of norepinephrine from synaptic neurons. Its vasoconstrictive ability is approximately 100 times weaker than that of epinephrine however, the duration of action is approximately 10 times longer. It is much less toxic than epinephrine, which allows it to be used widely in medicine. 

Use cautiously in people with acute or chronic respiratory impairment, particularly children, because phenothiazines may suppress the cough reflex. If hypotension occurs, epinephrine is not recommended because phenothiazines may reverse its usual pressor effect and cause a paradoxical further lowering of blood pressure. Because these drugs have an antiemetic action, they may obscure signs of intestinal obstruction, brain tumor, or overdosage of toxic drugs. 

Cardiovascular Effects. Most studies of humans exposed to carbon tetrachloride by inhalation have not detected significant evidence of cardiovascular injury, even at exposure levels sufficient to markedly injure the liver and/or kidney. Changes in blood pressure, heart rate, or right- sided cardiac dilation have sometimes, but not always, been observed (Ashe and Sailer 1942 Guild et al. 1958 Kittleson and Borden 1956 Stewart et al. 1961 Umiker and Pearce 1953), and are probably secondary either to fluid and electrolyte retention resulting from renal toxicity, or to central nervous system effects on the heart or blood vessels. Carbon tetrachloride also may have the potential to induce cardiac arrhythmias by sensitizing the heart to epinephrine, as has been reported for various chlorinated hydrocarbon propellants (Reinhardt et al. 1971). 

The most commonly used vasoconstrictors, the sympathomimetic drugs, are often added to local anesthetics to delay absorption of the anesthetic from its injection site. By slowing absorption, these drugs reduce the anesthetic s systemic toxicity and keep it in contact with nerve fibers longer, thereby increasing the drug s duration of action. Administration of lidocaine 1% with epinephrine results in the same degree of blockade as that produced by lidocaine 2% without the vasoconstrictor. 

D. Epinephrine is by far the most commonly employed vasoconstrictor. Phenylephrine is occasionally used with procaine for dental procedures. Levonordefrin is also used rarely in dental procedures. Dopamine has no vasoconstrictor activity. Cocaine is itself a local anesthetic with some vasoconstrictor properties. However, cocaine, because of its abuse potential and toxicity, is seldom used. Its only use is topical. 

Local anesthetics are frequently coadministered with vasoconstrictor molecules such as epinephrine. Normally, they are applied or injected locally and then taken up by local blood vessels into the systemic circulation, ultimately leading to their metabolic breakdown. The co-administration of a vasoconstrictor decreases the systemic absorption of the local anesthetic, thereby increasing its effective half-life in the area of administration and decreasing the probability of systemic toxicity (i.e., cardiac toxicity) secondary to systemic distribution. 

This is an amide local anaesthetic and is widely used on account of its rapid onset, medium duration of effect, and low toxicity. It is less highly protein-bound than the longer-acting amides (Table 5.1) but it has a useful duration of effect and is the most versatile of all local anaesthetics. It is of intermediate potency and has less toxic potential than bupivacaine. It is available in aqueous solution as the hydrochloride salt in concentrations of 0.5-2.0% with and without adrenaline (epinephrine). Topical preparations are also available as gels or aerosols in 2-4% concentrations. 

When used for spinal anaesthesia, 0.75% ropivacaine produces less intense sensory and motor block than 0.5% bupivacaine. It is suitable for regional, spinal and epidural block but not for regional intravenous anaesthesia. The addition of adrenaline (epinephrine) does not prolong the duration of anaesthesia in brachial plexus or epidural block. Ropivacaine is indistinguishable from bupivacaine when used in obstetric anaesthesia. Its direct myocardial toxicity is somewhat less than that of bupivacaine. 

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