Differing electrophysiological effects of class IA, IB and IC antiarrhythmic drugs on guinea-pig sinoatrial node

Standard microelectrode techniques were used to study the effects of class IA (quinidine, disopyramide, procainamide), IB (lignocaine, mexiletine, tocainide) and IC (flecainide, encainide, lorcainide) antiarrhythmic drugs on action potentials in spontaneously beating sino-atrial node cells from guinea-pigs. The IA drugs all produced significant slowing of spontaneous rate in therapeutic concentrations. The IB agents did so only in concentrations well above therapeutic levels and the IC drugs were of intermediate potency. All nine drugs markedly slowed the repolarization rate and this was the major mechanism of sinus slowing for the IA and IC compounds. The IB drugs shared this effect but prolongation of phase 4 by reduction of the slope of diastolic depolarization was also a prominent feature of their action.     

Coupling interval-related effects of class I antiarrhythmic drugs, mexiletine, cibenzoline and disopyramide, on ventricular activation in canine myocardial infarction.

Time-dependent inhibition of sodium channels by class I antiarrhythmic drugs has been observed in isolated cardiac muscles or cells. We examined coupling interval-related effects of class I antiarrhythmic drugs, mexiletine, cibenzoline and disopyramide, on ventricular activation in canine infarcted myocardium. A ventricular stimulation with various coupling intervals was applied to the right ventricle, and activation delays (time intervals between the initiation of a deflection and the final rapid deflection of a bipolar electrocardiogram) of infarcted and normal zones were measured. The premature stimulation produced a delayed activation and in some animals, caused reentrant beats. Mexiletine (3 and 10 mg/kg), cibenzoline (1 and 4 mg/kg) and disopyramide (1 and 4 mg/kg) further enhanced or blocked the delayed activation. The effects of these drugs were more marked at shorter coupling intervals, although cibenzoline and disopyramide showed significant effects also at long coupling intervals. The effect of these drugs on the activation in the normal zone was less than that in the infarcted zone. In conclusion, mexiletine, cibenzoline and disopyramide showed a coupling interval-related depression of delayed activation in infarcted myocardium, which may be a reflection of their time-dependent inhibition of sodium channels.     

Molecular action of class I antiarrhythmic drugs and clinical implications.

This report briefly reviews the advance in our knowledge of cellular electrophysiological effects of membrane stabilizer antiarrhythmic drugs (sodium channel blockers) including some new ones. The class I drugs block cardiac sodium channels and differ in the kinetics of the interaction with sodium channels and in the actions on the repolarization phase. The class I drugs can be subdivided into subclasses (I a,b,c). This review focuses on the interaction of these drug with sodium channels and the molecular models of their action. The interaction of class I drugs with the sodium channel receptor is influenced by the state of the myocardium (pH, ischaemia) and by other drugs as well. The clinical implications of different actions of sodium channel blockers, alone and in combination, and their proarrhythmic effects are summarized.     

Potentially significant drug interactions of class III antiarrhythmic drugs.

Class III antiarrhythmic drugs, especially amiodarone (a broad-spectrum antiarrhythmic agent), have gained popularity for use in clinical practice in recent years. Other class III antiarrhythmic drugs include bretylium, dofetilide, ibutilide and sotalol. These agents are effective for the management of various types of cardiac arrhythmias both atrial and ventricular in origin.Class III antiarrhythmic drugs may interact with other drugs by two major processes: pharmacodynamic and pharmacokinetic interactions. The pharmacodynamic interaction occurs when the pharmacological effects of the object drug are stimulated or inhibited by the precipitant drug. Pharmacokinetic interactions can result from the interference of drug absorption, metabolism and/or elimination of the object drug by the precipitant drug.Among the class III antiarrhythmic drugs, amiodarone has been reported to be involved in a significant number of drug interactions. It is mainly metabolised by cytochrome P450 (CYP)3A4 and it is a potent inhibitor of CYP1A2, 2C9, 2D6 and 3A4. In addition, amiodarone may interact with other drugs (such as digoxin) via the inhibition of the P-glycoprotein membrane transporter system, a recently described pharmacokinetic mechanism of drug interactions.Bretylium is not metabolised; it is excreted unchanged in the urine. Therefore the interactions between bretylium and other drugs (including other antiarrhythmic drugs) is primarily through the pharmacodynamic mechanism.Dofetilide is metabolised by CYP3A4 and excreted by the renal cation transport system. Drugs that inhibit CYP3A4 (such as erythromycin) and/or the renal transport system (such as triamterene) may interact with dofetilide.It appears that the potential for pharmacokinetic interactions between ibutilide and other drugs is low. This is because ibutilide is not metabolised by CYP3A4 or CYP2D6. However, ibutilide may significantly interact with other drugs by a pharmacodynamic mechanism.Sotalol is primarily excreted unchanged in the urine. The potential for drug interactions due to hepatic enzyme induction or inhibition appears to be less likely. However, a number of drugs (such as digoxin) have been reported to interact with sotalol pharmacodynamically.If concurrent use of a class III antiarrhythmic agent and another drug cannot be avoided or no published studies for that particular drug interaction are available, caution should be exercised and close monitoring of the patient should be performed in order to avoid or minimise the risks associated with a possible adverse drug interaction.     

Selectivity of class I antiarrhythmic agents, disopyramide, pirmenol, and pentisomide for peripheral muscarinic M2 and M3 receptors.

The interactions of the class I antiarrhythmic agents, disopyramide, pirmenol, and pentisomide with peripheral muscarinic receptors were investigated by binding assay with [3H]N-methylscopolamine ([3H]NMS) as a ligand. All the agents inhibited the specific [3H]NMS binding to membrane preparations obtained from guinea pig submandibular gland (SG) and urinary bladder (UB) smooth muscle. The competition curves of these agents for [3H]NMS binding to SG membranes were monophasic, indicating competition with [3H]NMS at a single site. Comparison of results with those of our previous binding experiments using guinea pig left atrial (LA) membranes, showed that pirmenol had sevenfold lower affinity for glandular-type muscarinic receptors (M3) than for cardiac-type muscarinic receptors (M2). On the other hand, the dissociation constants (Ki) for disopyramide and pentisomide in SG were comparable to the high-affinity Ki values for these agents at M2 receptors. The competition curves of the three agents for [3H]NMS binding to UB membranes were biphasic and showed high- and low-affinity states of binding. The high- and low-affinity Ki values for pirmenol in UB were similar to its Ki values at M2 and M3 receptors obtained in LA and SG, respectively. The high-affinity Ki values for disopyramide and pentisomide were consistent with the respective Ki values determined in SG, whereas the low-affinity binding sites for these agents were presumably the result of their allosteric interactions with the receptors. All agents at higher concentrations slowed the dissociation of [3H]NMS elicited by an excess of atropine in both UB and SG, thus indicating allosteric interactions.(ABSTRACT TRUNCATED AT 250 WORDS)     

An HPLC method for the simultaneous quantitation of quinidine, procainamide, N-acetylprocainamide, and disopyramide

A high performance liquid chromatographic method is reported, which incorporates three internal standards (I-cinchonidine, N-propylprocainamide, and para-chlorodisopyramide) for the simultaneous quantitation of four commonly prescribed antiarrhythmic drugs: quinidine, procainamide, N-acetylprocainamide, and disopyramide. Compounds were separated using combined ion-pairing and adsorption chromatography on a silica column. Inter-run variation was 5.9 CV% for all drugs.     

Poisoning due to pyrethroids

The first pyrethroid pesticide, allethrin, was identified in 1949. Allethrin and other pyrethroids with a basic cyclopropane carboxylic ester structure are type I pyrethroids. The insecticidal activity of these synthetic pyrethroids was enhanced further by the addition of a cyano group to give alpha-cyano (type II) pyrethroids, such as cypermethrin. The finding of insecticidal activity in a group of phenylacetic 3-phenoxybenzyl esters, which lacked the cyclopropane ring but contained the alpha-cyano group (and hence were type II pyrethroids) led to the development of fenvalerate and related compounds. All pyrethroids can exist as at least four stereoisomers, each with different biological activities. They are marketed as racemic mixtures or as single isomers. In commercial formulations, the activity of pyrethroids is usually enhanced by the addition of a synergist such as piperonyl butoxide, which inhibits metabolic degradation of the active ingredient. Pyrethroids are used widely as insecticides both in the home and commercially, and in medicine for the topical treatment of scabies and headlice. In tropical countries mosquito nets are commonly soaked in solutions of deltamethrin as part of antimalarial strategies. Pyrethroids are some 2250 times more toxic to insects than mammals because insects have increased sodium channel sensitivity, smaller body size and lower body temperature. In addition, mammals are protected by poor dermal absorption and rapid metabolism to non-toxic metabolites. The mechanisms by which pyrethroids alone are toxic are complex and become more complicated when they are co-formulated with either piperonyl butoxide or an organophosphorus insecticide, or both, as these compounds inhibit pyrethroid metabolism. The main effects of pyrethroids are on sodium and chloride channels. Pyrethroids modify the gating characteristics of voltage-sensitive sodium channels to delay their closure. A protracted sodium influx (referred to as a sodium 'tail current') ensues which, if it is sufficiently large and/or long, lowers the action potential threshold and causes repetitive firing; this may be the mechanism causing paraesthesiae. At high pyrethroid concentrations, the sodium tail current may be sufficiently great to prevent further action potential generation and 'conduction block' ensues. Only low pyrethroid concentrations are necessary to modify sensory neurone function. Type II pyrethroids also decrease chloride currents through voltage-dependent chloride channels and this action probably contributes the most to the features of poisoning with type II pyrethroids. At relatively high concentrations, pyrethroids can also act on GABA-gated chloride channels, which may be responsible for the seizures seen with severe type II poisoning. Despite their extensive world-wide use, there are relatively few reports of human pyrethroid poisoning. Less than ten deaths have been reported from ingestion or following occupational exposure. Occupationally, the main route of pyrethroid absorption is through the skin. Inhalation is much less important but increases when pyrethroids are used in confined spaces. The main adverse effect of dermal exposure is paraesthesiae, presumably due to hyperactivity of cutaneous sensory nerve fibres. The face is affected most commonly and the paraesthesiae are exacerbated by sensory stimulation such as heat, sunlight, scratching, sweating or the application of water. Pyrethroid ingestion gives rise within minutes to a sore throat, nausea, vomiting and abdominal pain. There may be mouth ulceration, increased secretions and/or dysphagia. Systemic effects occur 4-48 hours after exposure. Dizziness, headache and fatigue are common, and palpitations, chest tightness and blurred vision less frequent. Coma and convulsions are the principal life-threatening features. Most patients recover within 6 days, although there were seven fatalities among 573 cases in one series and one among 48 cases in another. Management is supportive. As paraesthesiae usually resolve in 12-24 hours, specific treatment is not generally required, although topical application of dl-alpha tocopherol acetate (vitamin E) may reduce their severity.     

Poisoning due to pyrethrins

The pyrethrins have a long and fascinating history. They were derived from dried chrysanthemum flower heads that were found to have pesticidal activity centuries ago. They comprise a complex mixture of six main chemicals. Commercial formulations usually contain piperonyl butoxide, which inhibits metabolic degradation of the active ingredients. Pyrethrins are readily absorbed from the gut and respiratory tract but poorly absorbed through skin. The active components are rapidly and extensively metabolised in the liver. Pyrethrins probably act on sodium channels resulting in nervous system overactivity. The possibility that they also induce hypersensitivity, which may be fatal when the respiratory tract is involved, has been debated for many years. A few clinical reports support this suggestion but the limited epidemiological evidence available is against it. The number of reports of toxicity caused by pyrethrins has greatly decreased over recent years. The pyrethrins are generally of low acute toxicity but convulsions may occur if substantial amounts are ingested. Two deaths from acute asthma have been attributed to pyrethrins and clinical reports suggest that they may also cause a variety of forms of dermatitis. Ocular exposure has resulted in corneal erosions. Management of pyrethrin toxicity is supportive and symptomatic.     

Differential analysis of the frequency-dependent effects of class 1 antiarrhythmic drugs according to periodical ligand binding: implications for antiarrhythmic and proarrhythmic efficacy.

The frequency-dependent block of cardiac sodium channels by class 1 antiarrhythmic drugs can be described by a periodical ligand binding process between drug molecules and channel binding sites. This predicts a linear relation between onset-rate constant of frequency-dependent block and diastolic interval as well as saturation of block with high stimulation rates. From both relationships, the binding kinetics (time constant, tau on) and saturation level of block (bdinf) can be estimated. This is exemplified for the frequency-dependent block (reduction of the maximal upstroke velocity of action potentials) induced by prajmaline (10(-6) M). In the same way, the frequency-dependent effects of 11 other class 1 drugs reported in the literature were analyzed and compared with each other. When the drugs are ranked with respect to their binding kinetics (tau on), there is a close relationship to the subclasses (1a, 1b, 1c), with 1b drugs exhibiting the fastest and 1c drugs the slowest kinetics. However, differences also exist in the saturation behavior of frequency-dependent block even within the same subclasses (1a and 1c). Thus, the class 1 drugs can also be subdivided in three other groups exhibiting clearly separated bands of block-frequency relations, with half-maximal saturation occurring at different stimulation rates. Our findings may have differential implications for the antiarrhythmic and proarrhythmic efficacy of class 1 drugs.     

Poisoning due to Pyrethroids

The first pyrethroid pesticide, allethrin, was identified in 1949. Allethrin and other pyrethroids with a basic cyclopropane carboxylic ester structure are type I pyrethroids. The insecticidal activity of these synthetic pyrethroids was enhanced further by the addition of a cyano group to give α-cyano (type II) pyrethroids, such as cypermethrin. The finding of insecticidal activity in a group of phenylacetic 3-phenoxybenzyl esters, which lacked the cyclopropane ring but contained the α-cyano group (and hence were type II pyrethroids) led to the development of fenvalerate and related compounds. All pyrethroids can exist as at least four stereoisomers, each with different biological activities. They are marketed as racemic mixtures or as single isomers. In commercial formulations, the activity of pyrethroids is usually enhanced by the addition of a synergist such as piperonyl butoxide, which inhibits metabolic degradation of the active ingredient. Pyrethroids are used widely as insecticides both in the home and commercially, and in medicine for the topical treatment of scabies and headlice. In tropical countries mosquito nets are commonly soaked in solutions of deltamethrin as part of antimalarial strategies. Pyrethroids are some 2250 times more toxic to insects than mammals because insects have increased sodium channel sensitivity, smaller body size and lower body temperature. In addition, mammals are protected by poor dermal absorption and rapid metabolism to non-toxic metabolites. The mechanisms by which pyrethroids alone are toxic are complex and become more complicated when they are co-formulated with either piperonyl butoxide or an organophosphorus insecticide, or both, as these compounds inhibit pyrethroid metabolism. The main effects of pyrethroids are on sodium and chloride channels. Pyrethroids modify the gating characteristics of voltage-sensitive sodium channels to delay their closure. A protracted sodium influx (referred to as a sodium ‘tail current’) ensues which, if it is sufficiently large and/or long, lowers the action potential threshold and causes repetitive firing; this may be the mechanism causing paraesthesiae. At high pyrethroid concentrations, the sodium tail current may be sufficiently great to prevent further action potential generation and ‘conduction block’ ensues. Only low pyrethroid concentrations are necessary to modify sensory neurone function. Type II pyrethroids also decrease chloride currents through voltage-dependent chloride channels and this action probably contributes the most to the features of poisoning with type II pyrethroids. At relatively high concentrations, pyrethroids can also act on GABA-gated chloride channels, which may be responsible for the seizures seen with severe type II poisoning. Despite their extensive world-wide use, there are relatively few reports of human pyrethroid poisoning. Less than ten deaths have been reported from ingestion or following occupational exposure. Occupationally, the main route of pyrethroid absorption is through the skin. Inhalation is much less important but increases when pyrethroids are used in confined spaces. The main adverse effect of dermal exposure is paraesthesiae, presumably due to hyperactivity of cutaneous sensory nerve fibres. The face is affected most commonly and the paraesthesiae are exacerbated by sensory stimulation such as heat, sunlight, scratching, sweating or the application of water. Pyrethroid ingestion gives rise within minutes to a sore throat, nausea, vomiting and abdominal pain. There may be mouth ulceration, increased secretions and/or dysphagia. Systemic effects occur 4–8 hours after exposure. Dizziness, headache and fatigue are common, and palpitations, chest tightness and blurred vision less frequent. Coma and convulsions are the principal life-threatening features. Most patients recover within 6 days, although there were seven fatalities among 573 cases in one series and one among 48 cases in another. Management is supportive. As paraesthesiae usually resolve in 12–24 hours, specific treatment is not generally required, although topical application of dl-α tocopherol acetate (vitamin E) may reduce their severity.     

Hemodynamic effects of penticainide (CM 7857), a novel class I antiarrhythmic drug--comparison with disopyramide

Penticainide (CM 7857) is a new class I antiarrhythmic agent, which has been shown to suppress ventricular arrhythmias by a specific effect on repolarization, shortening the action potential duration. To assess acute hemodynamic effects of penticainide and to compare them to those of disopyramide, 20 patients with normal left ventricular function were studied by simultaneous left and right heart catheterization before as well as 5 and 30 min after intravenous drug administration (1.5 mg/kg for both compounds) in a randomized fashion. After penticainide, a maximal negative inotropic effect was noted at the end of the 5 min infusion, as reflected by reductions in stroke index and parameters of contractility despite increases in vascular resistances. These changes returned to baseline after 30 min except for ejection fraction, which was still lower than at baseline. After disopyramide, similar hemodynamic drug effects were observed that were greater than after penticainide, leading to a moderate tachycardia immediately after drug infusion. In addition, all parameters of contractility as well as stroke index were still significantly reduced 30 min after disopyramide, but not after penticainide. Thus, the hemodynamic profiles of both drugs tested were similar, but the negative inotropic effect of penticainide was less marked and of shorter duration than that of disopyramide in an equipotent antiarrhythmic dose. Penticainide may therefore be used in treatment of acute ventricular arrhythmias, but it should be administered with caution in patients with depressed left ventricular function.     

Poisoning due to Pyrethrins

The pyrethrins have a long and fascinating history. They were derived from dried chrysanthemum flower heads that were found to have pesticidal activity centuries ago. They comprise a complex mixture of six main chemicals. Commercial formulations usually contain piperonyl butoxide, which inhibits metabolic degradation of the active ingredients. Pyrethrins are readily absorbed from the gut and respiratory tract but poorly absorbed through skin. The active components are rapidly and extensively metabolised in the liver. Pyrethrins probably act on sodium channels resulting in nervous system overactivity. The possibility that they also induce hypersensitivity, which may be fatal when the respiratory tract is involved, has been debated for many years. A few clinical reports support this suggestion but the limited epidemiological evidence available is against it. The number of reports of toxicity caused by pyrethrins has greatly decreased over recent years. The pyrethrins are generally of low acute toxicity but convulsions may occur if substantial amounts are ingested. Two deaths from acute asthma have been attributed to pyrethrins and clinical reports suggest that they may also cause a variety of forms of dermatitis. Ocular exposure has resulted in corneal erosions. Management of pyrethrin toxicity is supportive and symptomatic.     

Influence of disopyramide, compared with procainamide and quinidine, on isolated dog arteries in response to transmural stimulation and norepinephrine

In helically cut strips of dog cerebral, coronary, and mesenteric arteries contracted with prostaglandin (PG) F2 alpha, disopyramide phosphate produced moderate contractions that were unaffected by phentolamine, chlorpheniramine, cinanserin, or aspirin. Procainamide and quinidine elicited only a slight contraction. Mesenteric arterial strips contracted with norepinephrine slightly contracted in response to disopyramide but significantly relaxed with procainamide and quinidine. The contractile response of mesenteric arterial strips to transmural electrical stimulation was attenuated by high concentrations (5 x 10(-5) M) of disopyramide or procainamide and by low concentrations of quinidine. Disopyramide-induced attenuation was greater in the response to high-frequency stimulation. Disopyramide at high concentrations potentiated the contractile response of mesenteric arteries to norepinephrine and tyramine, while, in contrast, procainamide and quinidine shifted the dose-response curve for norepinephrine to the right. Treatment with procainamide and quinidine, but not with disopyramide, protected alpha-adrenoceptors from persistent blockade by phenoxybenzamine; quinidine was far more effective than procainamide. It may be concluded that disopyramide possesses a nonspecific vasoconstricting action but not an alpha-adrenoceptor blocking property, whereas quinidine and procainamide show a reversible, competitive alpha-adrenoceptor antagonism. Different hemodynamic actions of these antiarrhythmics in situ appear to be related to such contrasting effects on arterial smooth muscle.     

Poisoning due to calcium antagonists. Experience with verapamil, diltiazem and nifedipine.

The calcium antagonists are a heterogeneous class of drugs which block the inward movement of calcium into cells through 'slow channels' from extracellular sites. By inhibiting phase 0 depolarisation in cardiac pacemaker cells and phase 2 plateau in myocardium, and by depressing calcium ion flux in smooth muscle cells of blood vessels, these agents may exert profound effects on the cardiovascular system, particularly in susceptible individuals or in overdose. Sinus node depression, impaired atrioventricular (AV) conduction, depressed myocardial contractility, and peripheral vasodilatation may result. Pharmacokinetic features of calcium antagonists include rapid and complete absorption from the gastrointestinal tract, with extensive first-pass hepatic metabolism yielding generally low bioavailability. The volume of distribution is generally large and protein binding is high. Elimination is almost entirely by the liver. Impaired renal function does not affect pharmacokinetics. Verapamil is the most potent inhibitor of cardiac conduction and contractility, with diltiazem also showing such effects. Nifedipine is the most potent vasodilator, but only occasionally impairs the sinus node or AV conduction. Significant pharmacodynamic effects are common during combination therapy with calcium antagonists, especially verapamil and beta-blockers. Verapamil may significantly elevate serum digoxin concentrations and may exert additive negative effects on chronotropism and dromotropism when this combination is used. Overdoses of calcium entry blockers are becoming more frequent and reflect an extension of the known pharmacodynamic profile of these agents. Typical features include confusion or lethargy, hypotension, sinus node depression and cardiac conduction defects. Onset of symptoms may be delayed if a sustained release preparation is ingested. Management of calcium antagonist overdose includes gut decontamination with lavage and activated charcoal. All symptomatic patients and patients with a history of ingesting a sustained release preparation should be admitted for ECG monitoring. If bradycardia and/or conduction defects contribute to hypotension, atropine or isoprenaline (isoproterenol) may accelerate the ventricular rate. Transvenous pacing may be required. Depressed myocardial contractility usually responds well to calcium chloride or calcium gluconate administration, but further inotropic support may be required. Peripheral vasodilation should be managed with intravenous fluids and a pressor agent such as dopamine or norepinephrine (noradrenaline).     

Population pharmacokinetics,protein binding and antiarrhythmic effects of disopyramide enantiomers in arrhythmic patients

Disopyramide (DP) is widely used as an antiarrhythmic agent. The antiarrhythmic effects of its enantiomers differ from each other and its metabolism and protein binding are also stereoselective. Population pharmacokinetic parameters of DP racemate, enantiomers (S(+)-DP, R(-)-DP), and their unbound concentrations (uDP, S(+)-uDP and R(-)-uDP) were analyzed using the nonlinear mixed effect model (NONMEM) program. Data were available from 108 points of 33 arrhythmic patients on maintenance therapy with DP racemate. We evaluated the factors to which pharmacokinetic parameters are attributed and the relationships between each serum concentration and the antiarrhythmic effect. A one-compartment model was fitted to the data using NONMEM. For DP, S(+)-DP and R(-)-DP, elimination rate constants (kes) were estimated as 0.0648, 0.0663 and 0.0691/h, respectively and the mean apparent volume of distribution (Vd/F) were estimated as 63.2, 54.1 and 71.6 l, respectively. Using the ke and Vd/F values estimated by NONMEM, time-concentration curves were well fitted to the observed data. Unbound fractions of both DP enantiomers showed nonlinearity and the binding ratio of S(+)-DP was 0.84 +/- 0.07, which was higher than that of R(-)-DP [0.70 +/- 0.11 (p < 0.01)]. Unbound fractions of both DP enantiomers correlated with alpha1-acid glycoprotein (AGP) (p < 0.01). On the other hand, using NONMEM, a significant proportion of the variability of Vd/F could be attributed only to AGP (p < 0.001). NONMEM was able to clarify the pharmacokinetic features in the protein binding of DP. Individual steady state concentrations were estimated by NONMEM using the Bayesian method. The average unbound concentrations of all nine responders were higher than those of the four non-responders, even though this difference was not significant. Unbound concentrations may reflect drug concentrations in the tissue, which suggests that these concentrations may indicate an antiarrhythmic effect rather than the total concentration.     

沙丁胺醇过量致中毒

1例30岁男性患者因与家属争吵后自服沙丁胺醇约300片（2mg／片）后急诊入院,自述有头晕、头痛、目眩、心悸及口干等。予催吐、导泻、口服药用炭片吸附毒物,纠正电解质紊乱及维持酸碱平衡,血液灌流联合血液透析等治疗。3d后症状好转出院。7d后随访,患者无不适。     

Poisoning due to chlorophenoxy herbicides

Chlorophenoxy herbicides are used widely for the control of broad-leaved weeds. They exhibit a variety of mechanisms of toxicity including dose-dependent cell membrane damage, uncoupling of oxidative phosphorylation and disruption of acetylcoenzyme A metabolism. Following ingestion, vomiting, abdominal pain, diarrhoea and, occasionally, gastrointestinal haemorrhage are early effects. Hypotension, which is common, is due predominantly to intravascular volume loss, although vasodilation and direct myocardial toxicity may also contribute. Coma, hypertonia, hyperreflexia, ataxia, nystagmus, miosis, hallucinations, convulsions, fasciculation and paralysis may then ensue. Hypoventilation is commonly secondary to CNS depression, but respiratory muscle weakness is a factor in the development of respiratory failure in some patients. Myopathic symptoms including limb muscle weakness, loss of tendon reflexes, myotonia and increased creatine kinase activity have been observed. Metabolic acidosis, rhabdomyolysis, renal failure, increased aminotransferase activities, pyrexia and hyperventilation have been reported. Substantial dermal exposure to 2,4-dichlorophenoxy acetic acid (2,4-D) has led occasionally to systemic features including mild gastrointestinal irritation and progressive mixed sensorimotor peripheral neuropathy. Mild, transient gastrointestinal and peripheral neuromuscular symptoms have occurred after occupational inhalation exposure. In addition to supportive care, urine alkalinization with high-flow urine output will enhance herbicide elimination and should be considered in all seriously poisoned patients. Haemodialysis produces similar herbicide clearances to urine alkalinization without the need for urine pH manipulation and the administration of substantial amounts of intravenous fluid in an already compromised patient.