Neuromuscular Blocking Drugs and the Critical Care Patient

As the management of critically ill and emergency patients intensifies and veterinary surgical procedures become more complex, more sophisticated methods of support are becoming necessary. Emergency and critical care patients are excellent candidates for the use of neuromuscular blocking drugs. The main advantage of the current generation of neuromuscular blocking drugs compared to earlier agents is that they provide muscle relaxation with little or no cardiovascular effects. The pharmacology and physiology of neuromuscular blocking drugs are discussed, and their use is described with specific references to critical care patients. Monitoring techniques are described and reversal of neuromuscular blockade as well as potential side effects and adverse reactions arediscussed.     

Calcium Channel Blockers in Veterinary Medicine

Calcium channel blockers are becoming increasingly popular in veterinary medicine for the treatment of systemic hypertension, cardiac arrhythmias, and hypertrophic cardiomyopathy. Calcium is vital to many cellular functions and thus stringent regulation of intracellular calcium concentrations is required. Pharmacologic manipulation of the regulatory mechanisms has the potential to alter cellular function in all body systems. In human medicine, calcium channel blockers are being evaluated for, among other things, use in treating glaucoma, deep vein thrombosis, and pulmonary hypertension, in renal transplantation, and for prevention of reperfusion injury. The potentially beneficial effects of these drugs have often been overshadowed by adverse effects including hypotension, inappetence, bradycardia, conduction abnormalities, and decreased cardiac output. With the introduction of sustained- release formulations (diltiazem) and 2nd generation calcium channel blockers (amlodipine) many of these effects have been attenuated or eliminated. This paper will review the functions of calcium and the calcium channels as well as discussing the classes and current and potential uses of the various calcium channel blockers.     

Treatment of congestive heart failure a neuroendocrine disorder

The understanding of heart failure is no longer based on a supply and demand model of pump failure. Rather, heart failure is seen as a complex pathophysiological process with activation of various neuroendocrine systems. The goals of treatment have changed towards modifying these counterproductive neuroendocrine systems and slowing myocardial maladaptation. Angiotensin converting enzyme inhibitors are the only licensed drugs in veterinary practice that have a direct effect on neurohormones in heart failure. The range of drug options in human medicine is greater and some of these drugs are also increasingly being used in veterinary cardiology practice. This review describes the neuroendocrine systems involved in heart failure and discusses the range of drugs available in human and veterinary medicine. In doing so, it concentrates on the evidence available from good quality randomised trials in both the veterinary field and, where relevant, the human medical field.     

Calcium channel blocker toxicity

Objective: Calcium channel blockers (CCB) are frequently prescribed for veterinary patients and the incidence of toxicosis secondary to these agents is increasing. The purpose of this review is to discuss toxicity of these agents and review therapeutic options. Etiology: Calcium plays a vital role in maintaining cellular functions within the cardiovascular system. Toxicosis secondary to these drugs can have deleterious effects on vascular tone, cardiac contractility, as well as electrical conduction in the heart. Diagnosis: The intitial diagnosis is often made based on history of ingestion, physical examination and electrocardiography. Definitive diagnosis of CCB overdose can be made via quantification of serum concentrations of the drug ingested. Therapy: Initial therapy should consist of inducing emesis and administration of activated charcoal. Other potential therapies include intravenous calcium, parasympatholytics, sympathomimetics, glucagon, insulin and dextrose, placement of a temporary pacemaker, or calcium channel agonists. Prognosis: There is little data on the outcome of CCB toxicosis. Aggressive management of these cases is necessary to try and minimize morbidity and mortality.     

Newer neuromuscular blockers. Is the practitioner ready for muscle relaxants?

Current research on the development of new neuromuscular blocking agents is directed towards producing agents that have a rapid onset of action and predictable duration of action and recovery times, with minimal hemodynamic effects. For the veterinary practitioner, these newer agents should be considered when muscle relaxation is required for certain surgical procedures. Care must be taken to monitor paralyzed patients appropriately to ensure adequate ventilation and anesthetic depth. Vigilant monitoring should exist during the recovery period for the development of muscle weakness from residual blockade and the ability to reverse the effects of neuromuscular blockade. The use of neuromuscular blocking agents in veterinary patients should continue to increase as newer drugs and better monitoring techniques are developed.     

Biochemistry and behaviour: systemic aspects of neurological disturbances

This article considers ways in which simple changes in plasma composition (especially in the concentration of Na⁺, Ca⁺⁺, Mg⁺⁺ and glucose) can initiate most of the symptoms usually associated with neurological disorders. The more complex deterioration of plasma composition inflicted by renal or hepatic failure is also discussed and related to behavioural abnormalities. Although most of the relevant clinical observations have been in man, the extent to which experimental animals demonstrate similar effects suggests that the importance of these conditions in veterinary medicine may be underestimated. Even if they are less frequent, they deserve attention because, in principal, they are easily diagnosed and, in contrast to other neural disturbances, readily reversible.     

药动/药效同步模型在兽用抗菌药物研究的应用概况

药动/药效同步模型是将药动学和药效学结合,用于研究药理效应随时间变化规律的一种模型。药动/药效同步模型在药理学和毒理学研究、临床应用及新药评价等领域得到越来越广泛的应用。随着抗菌药物的发展,耐药性问题日益成为全球关注的焦点。将药动/药效同步模型引入兽药研究中,不仅能够优化给药方案,避免细菌耐药性的产生,也能够为新药的开发提供研究基础。论文对兽用抗菌药物的分类、药动/药效同步模型的研究方法及其在国内外兽药研究中的应用现状进行综述,以期为药动/药效同步模型的兽医临床应用提供参考。     

Enantioselective behaviour of drugs used in domestic animals: a review

The chirality of drugs, with particular reference to agents used in veterinary medicine, is reviewed. Basic concepts of chirality and aspects of the methodology for the separation of enantiomers are considered. Chiral compounds are in common use in animals and their pharmacological actions and side-effects (pharmacodynamics) and absorption into and fate within the body (pharmacokinetics) are of fundamental importance; pharmacodynamic and pharmacokinetic properties of enantiomeric pairs commonly differ and this has major implications for their effective and safe therapeutic use. As examples of the particular significance of chirality in veterinary medicine, the following drug classes are reviewed; benzimidazole anthelmintics, cloprostenol, verapamil, ketamine, halogenated hydrocarbon anaesthetics and 2-arylpropionic acid anti-inflammatory drugs. The implications of chirality for drug product development and approval by registration authorities are discussed.     

Advantages of and guidelines for using neuromuscular blocking agents.

Neuromuscular blocking agents, although not commonly used in veterinary practice, should be considered when muscle relaxation is needed to facilitate surgical exposure and minimize tissue trauma. These drugs should be administered only once respiration has been controlled and anesthetic agents have been administered to induce unconsciousness and analgesia. Following administration of neuromuscular blocking drugs, neuromuscular and cardiovascular function must be monitored.     

The efficacy and safety of milrinone for treating heart failure in dogs

Milrinone has been studied in a variety of situations. In experimental dogs it has been documented to increase contractility to a similar degree as beta-receptor agonists and to produce mild arteriolar dilation in dogs. In canine patients with heart failure, milrinone produces demonstrable improvement in echocardiographic ventricular function and hemodynamic variables. In addition, it improves clinical signs in these patients, improving their quality of life. Milrinone is superior to digoxin as evidenced by the improvement in clinical signs noted in dogs that were unresponsive or no longer responding to digoxin administration. There is no doubt that milrinone improves short-term prognosis and in so doing prolongs life. Many of the patients that the author has observed would not have gone home without the benefits of milrinone. Milrinone's effects on long-term survival cannot be assessed, but its effects on survival time are certainly not dramatic enough to be evident without a comparison population. Therefore, milrinone administration should be considered palliative, as is administration of all other cardiovascular medications for heart failure. In addition to its beneficial effects, milrinone also appears to be relatively safe when compared with the alternative of digoxin administration. Fatal events attributable to milrinone administration are rare, and those directly attributable to enhanced ventricular arrhythmia can generally be avoided by monitoring an electrocardiogram after initial milrinone administration commences. Milrinone does not increase the incidence of sudden death in Doberman Pinschers. It is possible that a small number of dogs with mitral regurgitation may develop mitral chordal rupture. For this reason and possibly others, milrinone probably will not be indicated in early heart failure due to mitral regurgitation when heart failure is readily responsive to diuretic administration. The risk-to-benefit ratio turns markedly in the favor of milrinone administration in the dog with mitral regurgitation that is partially or completely refractory to other cardiovascular drugs. Milrinone appears to be a more effective and safer positive inotrope for long-term treatment of dogs with congestive heart failure than drugs currently available. The author and all the investigators involved in the milrinone clinical trials hope that it will soon be available for use by the veterinary community.     

New perspectives in cardiology: pharmacodynamic classification of antiarrhythmic drugs

Recent advancements in cardiac pharmacology and physiology have led to the identification of many new antiarrhythmic drugs and a better understanding of basic arrhythmogenic mechanisms. These parallel developments prompted a new nomenclature system for classifying the clinically important antiarrhythmic drugs according to their predominant electrophysiologic actions in cardiac cells. Antiarrhythmic drugs are now grouped into 4 main classes: classes I through IV. Class I agents comprise the standard membrane-stabilizing drugs such as lidocaine, quinidine, and procainamide; newer class I agents include disopyramide, aprindine, tocainide, and flecainide. Class II agents decrease sympathoadrenal excitation of the heart, and the clinically relevant members of this type act through blockade of the cardiac beta 1-adrenergic receptors; propranolol is the prototype. Class III agents selectively prolong the cardiac action potential and refractory period, and bretylium and amiodarone represent this group. Class IV agents are the calcium entry blocking drugs such as verapamil. An understanding of this classification system is essential to the internist and cardiologist who are beset with an emerging array of new antiarrhythmic drugs and affiliated pharmacodynamic terminologies.     

Pharmacology and pharmacokinetics of drugs used to treat cardiac disease in horses

The rational therapy of cardiovascular disease in horses requires a thorough knowledge of the pharmacology and pharmacokinetics of several specific drugs (digitalis, digoxin). Calcium solutions, dopamine, and dobutamine are frequently used to treat congestive heart failure in horses. Quinidine, procainamide, lidocaine, and propranolol are used to treat a variety of supraventricular and ventricular arrhythmias. Furosemide, a highly potent loop diuretic, is used to eliminate edema and promote diuresis. A thorough understanding of the applied pharmacology, dosage recommendations, toxicity, and practical considerations must be attained before these drugs can be used effectively.     

Use of intravenous lidocaine to prevent reperfusion injury and subsequent multiple organ dysfunction syndrome

Objective: The objective of this article is to review the human and veterinary literature and provide evidence for the potential beneficial effects of intravenous (IV) lidocaine hydrochloride in preventing post‐ischemic–reperfusion injury, the systemic inflammatory response syndrome (SIRS), and subsequent multiple organ dysfunction syndrome (MODS). Human data synthesis: Lidocaine is a local anesthetic and antiarrhythmic agent that has been used for years in human and veterinary medicine for the treatment of ventricular dysrhythmias associated with blunt cardiac trauma, myocardial ischemia, and cardiac surgery. More recently, the drug has been touted as a scavenger of reactive oxygen species (ROS), and has been used to prevent reperfusion dysrhythmias after treatment of myocardial infarction, cross‐clamping of the aorta, and in trauma medicine. Veterinary data synthesis: Although no clinical experiments with prophylactic intravenous lidocaine exist in veterinary medicine, there is a large body of evidence from experimental animals that support the use of lidocaine as a Na⁺/Ca²⁺ channel blocker, superoxide and hydroxyl radical scavenger, inflammatory modulator, and potent inhibitor of granulocyte functions. Lidocaine is being used in some clinical situations in an attempt to prevent the SIRS in veterinary trauma patients. ^a,b, ^a,b Conclusions: A large body of experimental evidence exists supporting the use of lidocaine as an anti‐oxidant and inflammatory modulator useful in preventing reperfusion injury. With the lack of cost‐effective and safe treatments for reperfusion injury in veterinary and human trauma medicine, the use of IV lidocaine to prevent the ensuing inflammatory response and MODS makes it an attractive addition to existing treatments. Therefore, it is essential that prospective clinical trials involving lidocaine as a treatment for prevention of reperfusion injury be performed in companion animals to demonstrate its safety and efficacy.     

Aldosterone receptor antagonists – how cardiovascular actions may explain their beneficial effects in heart failure

Ovaert, P., Elliott, J., Bernay, F., Guillot, E., Bardon, T. Aldosterone receptor antagonists – how cardiovascular actions may explain their beneficial effects in heart failure. J. vet. Pharmacol. Therap. 33 , 109–117. Historically, aldosterone receptor antagonists (ARA) have been classified as ‘potassium sparing diuretics’. However, the positive effect of spironolactone, the most extensively studied ARA, on morbidity and mortality observed in humans suffering cardiac insufficiency could not be explained by the renal effect of the drug alone, and a pivotal clinical study has led to extensive research. Many experimental studies have demonstrated that ARA have previously unexpected beneficial effects on the cardiovascular system including reduction in remodelling of the vascular smooth muscle cells and myocytes and improvement of endothelial cell dysfunction in heart failure. These effects improve vascular compliance and slow down the progression of left ventricular dysfunction and end‐organ damage. Furthermore, aldosterone receptor blockade also restores the baroreceptor reflex, improving heart rate variability in heart failure in humans. Some of these effects have been demonstrated in dog models of cardiac disease and so justified further investigation of the potential benefit of ARA in dogs with congestive heart failure (CHF). Positive effects of spironolactone on morbidity and mortality appear to have been seen in studies conducted in dogs suffering from naturally occurring CHF. In addition, eplerenone has been shown to have benefits in canine models of heart failure. The precise mechanisms by which ARA produce these beneficial effects in dogs remain to be determined but this group of drugs clearly provide therapeutic actions out‐with their diuretic effects.     

Hemodynamic Effects of Atropine, Dobutamine, Nitroprusside, Phenylephrine, and Propranolol in Conscious Horses

The authors investigated the cardiovascular effects of low doses of nitroprusside, dobutamine, and phenylephrine and a beta-adrenergic blocking dose of propranolol in conscious, healthy horses with and without prior atropine administration. A parasympathetic blocking dose of atropine produced significant increases in heart rate and arterial pressures, and decreased stroke volume, ejection fraction, pulse pressure, and right-ventricular end-diastolic pressure and volume. Cardiac output was not changed by atropine administration. Nitroprusside reduced arterial pressures to a greater extent in atropinized horses but increased heart rate in both atropinized and non-atropinized horses. Dobutamine increased mean arterial pressure in both non-atropinized and atropinized horses but increased heart rate, diastolic arterial pressure, and systemic vascular resistance only in atropinized horses. Propranolol did not affect any of the hemodynamic variables that were measured. Phenylephrine, in the presence of beta-adrenergic blockade, increased mean arterial pressure and reduced cardiac output. This study showed that low doses of nitroprusside, dobutamine, and phenylephrine produce significant hemodynamic effects in conscious, healthy horses and that these effects are modified by prevailing parasympathetic tone.     

Evidence for or against efficacy of beta-blockers and aspirin for management of feline cardiomyopathies.

Feline myocardial diseases today are largely represented by disorders involving LV hypertrophy. They may be attended by arrhythmias, congestive heart failure, systemic hypertension, thromboembolic complications, and sudden death. These structural myocardial disorders and their hemodynamic and electrocardiographic derangements may cause or result in variable degrees of diastolic dysfunction. Propranolol and aspirin represent two agents commonly employed to treat feline cardiomyopathies for more than 15 years. Nevertheless, clinical data describing their effect on morbidity and mortality are lacking. It is likely that propranolol administered at moderate to high doses effects favorable responses in some cats with clinical signs attributable to severe hypertrophy, outflow obstruction, or tachyarrhythmias. It is unknown whether clinical improvements are due to direct myocardial effects or (more likely) secondary responses to a beta-adrenergic blockade reduction in heart rate or contractility. Personal experience also indicates that high numbers of cats have received the drug for many years in combination with other therapies (especially furosemide) and remain in a compensated state of heart failure without untoward drug effects. On the other hand, many cardiomyopathic cats experience heart failure, arrhythmias, and death despite treatment with beta-blocking agents. Feline thromboembolism is a devastating complication of cardiomyopathic disorders. Until or unless the primary cause(s) of current diseases is elucidated to promote disease reversal, factors responsible for thrombus formation will accompany the heart diseases, protected from effective management. It appears unlikely that aspirin as currently recommended produces any obvious benefit in treating or preventing thromboembolism. Modifications of therapeutic protocols prescribing these frequently used drugs await well-constructed clinical trials evaluating their efficacy with respect to cardiovascular morbidity and mortality.     

兽用中药生物学检测方法与评价技术

兽用中药化学成分复杂、药效物质基础研究薄弱,质量控制与评价一直是其研究的难点。现行的以理化检测方法为主的质量控制手段难以满足现代中兽医药发展的需要,难以很好地反映中药的有效性、安全性。本文阐述了显微、DNA条形码分子鉴定、基因芯片等生物学检测方法与评价技术在兽用中药质量控制中的应用价值,建议加强生物学相关检测及评价技术的研究和应用,弥补传统质控方法的不足,促进兽用中药质量控制水平的全面提升。     

A review of clinical approaches to antagonism of alpha2‐adrenoreceptor agonists in the horse

Alpha₂‐adrenoceptor agonists xylazine, romifidine, detomidine and, in some cases, medetomidine and dexmedetomidine, are fundamental drugs used in equine practice. There are situations where the undesirable pharmacodynamic effects (ataxia, prolonged sedation, bradycardia and ileus) or accidental overdose of these drugs may need to be antagonised. The α₂‐adrenoceptor antagonists tolazoline, yohimbine and atipamezole can be used to antagonise undesirable effects. However, despite being effective, α₂‐adrenoceptor antagonists are also not without undesirable pharmacodynamic effects. Excitement, muscle trembling and triggered inappropriate stress responses are a few of the more serious undesirable effects. Horses demonstrate a variable response to the antagonists thus recommending dose rates become fraught with difficulty. It is therefore recommended that the α₂‐adrenoceptor antagonist should be titrated to the desired clinical effect. Consequently, other reversal agents, such as anticholinergics (atropine, glycopyrrolate and hyoscine), have been administered for the treatment of α₂‐adrenoceptor agonist‐induced bradycardia. Anticholinergics cannot be recommended for routine use in horses due to the undesirable cardiovascular effects and potentiation of α₂‐adrenoceptor agonist‐induced gastrointestinal hypomotility. Novel peripheral acting α₂‐adrenoceptor antagonists, such as MK‐467, are currently under scrutiny in veterinary anaesthesia in an effort to antagonise the undesirable effects of α₂‐adrenoceptor agonists without compromising on the level of sedation. This review examines the current literature on the α₂‐adrenoceptor antagonists used in horses and makes recommendations on how to use these drugs safely in an attempt to prevent undesirable pharmacodynamic effects.     

The pharmacologic spectrum of furosemide

Objective: To review the clinical spectrum and mechanisms of action of furosemide in human and small animal veterinary patients. Data sources: Review of human and veterinary literature. Data synthesis: Furosemide is used primarily for its properties as a loop diuretic; however, it has many other actions that may be clinically applicable. Furosemide has a vasodilatory effect that precedes diuresis that may confer its immediate benefit in patients with volume overload. Furosemide can be inhaled to relieve dyspnea in patients with bronchospasm. Furosemide also shows promise as an adjunct to antiseizure therapy to help control epilepsy, status epilepticus, and acute ischemic damage related to seizures. It has activity as an antioxidant, iodine depletive, and may increase thoracic lymph duct flow. Reported furosemide side effects include altered drug metabolism, electrolyte depletion, ototoxicity, mucociliary impairment, endocrine and exocrine pancreatic effects, delayed wound healing, sulfonamide toxicity, and thyroid binding interference. It is worthwhile to consider the implications of these effects when using furosemide either alone or in combination with other drugs. Conclusions: Despite the research in animal models that demonstrates a wide spectrum of pharmacologic activity, furosemide has not been widely recognized or used clinically in veterinary medicine except as a loop diuretic.     

ACVIM small animal consensus statement on safe use of cytotoxic chemotherapeutics in veterinary practice

The purpose of this report is to offer a consensus opinion of ACVIM oncology diplomates and technicians on the safe use of cytotoxic chemotherapeutics in veterinary practice. The focus is on minimizing harm to the personnel exposed to the drugs: veterinary practitioners, veterinary technicians, veterinary staff, and pet owners. The safety of the patient receiving these drugs is also of paramount importance, but is not addressed in this statement. Much of the information presented is based on national recommendations by Occupational Safety and Health Administration, National Institute for Occupational Safety and Health, United States Pharmacopeia, and other published regulations. These directives reflect an abundance of caution to minimize exposure to medical personnel, but large‐scale studies about the consequences of long‐term occupational exposure are not available in veterinary medicine. Challenges in the delivery of optimal treatment safely and economically to veterinary patients in general practice without access to a veterinary oncologist or other specialist, because of costs or proximity, remain.