Drug interactions with neuromuscular blockers

Drugs administered to patients undergoing anaesthesia may complicate the use of the neuromuscular blockers that are given to provide good surgical conditions. The various sites of interaction include actions on motor nerve conduction and spinal reflexes, acetylcholine (ACh) synthesis, mobilisation and release, sensitivity of the motor end plate to ACh and the ease of propagation of the motor action potential. In addition, many drugs affect the pharmacokinetics of neuromuscular blockers, especially as most drugs depend to a greater or lesser extent upon renal excretion. The clinically significant interaction between nondepolarisers and depolarisers may be due to blockade of the pre-synaptic nicotinic receptors by the depolarisers, leading to decreased ACh mobilisation and release. Synergism between nondepolarisers probably results from post-synaptic receptor mechanisms. Volatile anaesthetic agents affect the sensitivity of the motor end-plate (post-synaptic receptor blockade) in addition to having effects on pre-synaptic nicotinic function. The effects of nondepolarisers are likely to be potentiated and their action prolonged by large doses of local anaesthetics due to depression of nerve conduction, depression of ACh formation, mobilisation and release, decreases in post-synaptic receptor channel opening times and reductions in muscular contraction. Most antibacterials have effects on pre-synaptic mechanisms. Procainamide and quinidine principally block nicotinic receptor channels. Magnesium has a marked inhibitory effect on ACh release. Calcium antagonists could theoretically interfere with neurotransmitter release and muscle contractility. Phenytoin and lithium decrease ACh release, whilst corticosteroids and furosemide (frusemide) tend to increase the release of the transmitter. Ecothiopate, tacrine, organophosphates, propanidid, metoclopramide and bambuterol depress cholinesterase activity and prolong the duration of the neuromuscular block. The probability of clinically significant interactions increases in patients receiving several drugs with possible effects on neuromuscular transmission and muscle contraction.     

Drug interactions and the clinical anaesthetist

In clinical practice, anaesthetists encounter many patients who are on concurrent medication which may have the potential to interact with drugs used during anaesthesia. Many patients are receiving as many as a dozen drugs of various kinds, thus, increasing the risk of a drug interaction occurring. Unfortunately anaesthetists tend not to report drug interactions which occur during anaesthesia--especially those of a minor nature such as flushing--and hence, the true number of drug interactions is unknown. We have developed a chart indicating the nature of important interactions that the anaesthetist may encounter.     

Drug interactions and antibiotics

Situations that require the use of systemic antibiotic therapy are common and drug interactions are potentially frequent. These interactions may be deleterious and lead to reduction of therapeutic index, enhancement of toxic risk or may be favourable, with optimization of pharmacokinetics or pharmacodynamics. The mechanisms of these interactions are discussed.     

Drug interactions in patients infected with human immunodeficiency virus

Patients with AIDS who are receiving optimal medical care, including combination therapy with antiretroviral agents and more effective prophylaxis and therapy for opportunistic infections and neoplasms, are surviving longer. However, the potential for drug interactions in these patients is increased because many of the currently used antibiotics and antiviral agents have profound effects on the hepatic cytochrome P-450 enzyme system, on renal tubular function, and on bone marrow function. In this AIDS Commentary, Dr. Piscitelli and colleagues have succinctly reviewed the current state of our knowledge regarding the potential for additive or synergistic drug interactions that can result in enhanced toxicity or, alternatively, augmented therapeutic benefit. Information on these interactions will become more important as more intensive and effective therapy becomes available for persons with far-advanced infection due to human immunodeficiency virus type 1.     

Drug interactions: regulatory aspects

Resuscitation skills were assessed in a group of 24 anaesthetists of varying experience using 3 pre-determined scenarios. Seventy-nine percent of participants were found to be competent at resuscitation following the guidelines suggested by the Resuscitation Council (UK) in 1989. No one grade of anaesthetist was found to be consistently poor at resuscitation. Anaesthetists by the nature of their jobs may maintain the skills and knowledge of cardiopulmonary resuscitation as well as other groups in the hospital.     

Drug interactions: keeping it straight

Drug interactions are common causes of treatment failure and adverse reactions. Patients who have a number of chronic disorders, patients who take many medications or patients who have impaired renal function are at increased risk for these problems. Special attention must be given to drugs that require blood level monitoring, because these agents have a narrow margin of safety. Drug interactions are especially likely to occur with enzyme inhibitors such as erythromycin, cimetidine, ciprofloxacin and metronidazole. Mechanisms of drug interactions include problems with absorption secondary to binding by antacids or other cations, interference with the distribution of drugs secondary to the displacement of highly protein-bound drugs, differences in metabolism secondary to variability of the cytochrome P450 enzyme system, and interaction-related problems with drug excretion by renal tubules. Antagonistic and synergistic reactions also need to be considered. Finally, the time course in which a given drug interaction is likely to occur must be taken into account when deciding whether the interaction is responsible for an adverse effect or treatment failure.     

Drug interactions in chronic prescription]

Although respiratory failures following exposure to waterproofing sprays have been reported worldwide, their mechanism remains unknown. In this study, we sorted each of 12 commercial waterproofing sprays into either the Toxic Group (No 1-4) or the Non-Toxic Group (No 5-12) and compared the pathological changes produced in the lungs of mice after their inhalation. Then we determined the diameters of each product's mist particles and their adhesion rates to cloth. The 4 products in the Toxic Group, reported as toxic to human beings, caused severe damage to mice lungs, whereas the 8 products in the Non-Toxic Group, not reported as toxic, caused little if any damage. The percentage of particle < or = 10 microns were significantly higher in the Toxic Group than in the Non-Toxic Group. The adhesion rate to cloth correlated to the mean particle diameter and was significantly lower in the Toxic Group than in the Non-Toxic Group. The toxic sprays generated mists of smaller particle diameter than the non-toxic sprays, suggesting that the mist particle diameters of waterproofing sprays are related to their toxicity.     

Drug interactions in human neuropathic pain pharmacotherapy

The effects of 0.3 mg/kg methylphenidate (MPH) and expectancy regarding medication on the performance and task persistence of 60 boys with attention deficit hyperactivity disorder (ADHD) were investigated. In a balanced-placebo design, boys in 4 groups (received placebo/drug crossed with told placebo/drug) completed the task in success and failure conditions. Medication improved participants' task persistence following failure. Participants' task performance was not affected by whether they thought they had received medication or placebo. Children made internal attributions for success and made external attributions for failure, regardless of medication or expectancy. These findings confirm previous reports that it is the pharmacological activity of MPH that affects ADHD children's self-evaluations and persistence. The results contradict anecdotal reports that MPH causes dysfunctional attributions and confirm previous studies showing that medication does not produce adverse effects on the causal attributions of children with ADHD.     

Antiparkinsonian agents. Drug interactions of clinical significance

Within the past 3 decades revolutionary changes have taken place in the pharmacological management of Parkinson's disease. Used alone, or often in combination, antiparkinsonian agents can dramatically and meaningfully ameliorate the symptoms of Parkinson's disease. However, with the development of effective therapeutic agents has come the potential for drug interactions; these interactions can produce consequences that range from the inconsequential to incapacitating and even life-threatening. Drug-drug interactions are not a major problem with either the anticholinergic medications or amantadine. However, cumulative anticholinergic toxicity may occur when multiple drugs with anticholinergic properties are utilised concomitantly, and amantadine toxicity can be triggered by drugs that impair its renal clearance. Gastric emptying and levodopa absorption can be significantly altered by medications and dietary contents. A rather extensive array of medications can interfere with dopaminergic function and thus produce clinical parkinsonism or impair the effectiveness of levodopa. The effectiveness of direct dopamine agonists can also be affected by a small group of agents. As a selective monoamine oxidase type B (MAO-B) inhibitor, selegiline (deprenyl) is free of the 'cheese-effect' when employed in recommended dosages. However, potentially life-threatening drug interactions, with both pethidine (meperidine) and with fluoxetine and other antidepressant medications, have been described, presumably occurring via serotonergic mechanisms. Awareness of the potential for drug interactions with antiparkinsonian agents, and prompt recognition of them when they do occur, is vital for the optimum clinical management of Parkinson's disease.     

Drug interactions with grapefruit juice. Extent, probable mechanism and clinical relevance

Concomitant intake with grapefruit juice increases the concentrations of many drugs in humans. The effect seems to be mediated mainly by suppression of the cytochrome P450 enzyme CYP3A4 in the small intestine wall. This results in a diminished first pass metabolism with higher bioavailability and increased maximal plasma concentrations of substrates of this enzyme. The effect was most pronounced in drugs with a high first pass degradation and in many cases has the clear potential to reach clinical relevance, as shown by an occasional change in drug effects or tolerability. For felodipine, nitrendipine, nisoldipine and saquinavir, the interaction was most marked with median increases of area under the curve (AUC) and/or the maximum (peak) plasma drug concentration after single-dose administration (Cmax) values exceeding 70% of respective control periods. Less pronounced, but possibly relevant, concentration increases were found for nifedipine, nimodipine, verapamil, cyclosporin, midazolam, triazolam and terfenadine. This list is not complete because many drugs have not been studied yet. The components of grapefruit juice which are the most probable causes of the interactions are psoralen derivatives, but the flavonoid naringenin may also contribute. Concomitant grapefruit juice intake does not generally decrease the variability of drug pharmacokinetic parameters. Therefore, it is recommended that patients refrain from drinking grapefruit juice when they are taking a drug that is extensively metabolised, unless a lack of interaction has already been demonstrated for the drug. It is also recommended that drugs possibly interacting with grapefruit juice should be appropriately labelled. A place for grapefruit juice as a drug-sparing agent in treatment involving expensive medicine cannot be derived from the information currently available on grapefruit juice interactions.     

Determination of antihistamines based on the formation of mixed aggregates with surfactants

In order to clarify how cytoskeletons and adhesion systems change through acquisition of metastatic capacity in a cancer cell, we examined the expressions of beta- and gamma-actin, the morphology of actin microfilaments and focal contacts, and also the expression of vinculin in a salivary gland adenocarcinoma cell clone cl-1, which acquired metastatic capacity, in comparison with its original clone HSGc lacking metastatic ability. Two-dimensional gel electrophoresis of Triton-insoluble fractions and combined Western blot analysis by immunostaining with anti actin-isoform antibodies showed that the expression of gamma-actin was somewhat lower than that of beta-actin in HSGc, and cl-1 expressed a comparable amount of beta-actin to HSGc, whereas gamma-actin expression by cl-1 was far less than that by HSGc. Northern blot analysis demonstrated that there was little difference in the level of beta-actin mRNA between HSGc and cl-1, while the level of gamma-actin was markedly decreased in cl-1 as compared with HSGc. In terms of morphology, cl-1 cells showed disruption of actin microfilaments and a decrease in the size and number of focal contacts on the cell surface. Furthermore, cl-1 showed decreased expression of vinculin, which became obscured even at the end of actin microfilaments. These results demonstrated that a decrease in gamma-actin, disruption of actin microfilaments, and suppression of focal contacts as well as vinculin take place in the transformation from a non-metastatic condition to a metastatic one in the human salivary gland adenocarcinoma cell clones. Thus, it was strongly suggested that these changes contribute to a decrease in cell adhesiveness and an increase in cell motility, which is probably a major cause for acquisition of metastatic potential.     

Systemic antifungal agents. Drug interactions of clinical significance

There are 3 main classes of systemic antifungals: the polyene macrolides (e.g. amphotericin B), the azoles (e.g. the imidazoles ketoconazole and miconazole and the triazoles itraconazole and fluconazole) and the allylamines (e.g. terbinafine). Other systemic antifungals include griseofulvin and flucytosine. Most drug-drug interactions involving systemic antifungals have negative consequences. The interactions of amphotericin B, flucytosine, griseofulvin, terbinafine and azole antifungals can be divided into the following categories: (i) additive dangerous interactions; (ii) modifications of antifungal kinetics by other drugs; and (iii) modifications of the kinetics of other drugs by antifungals. Amphotericin B and flucytosine mainly interact with other agents pharmacodynamically. Clinically important drug interactions with amphotericin B cause nephrotoxicity, hypokalaemia and blood dyscrasias. The most important drug interaction of flucytosine occurs with myelotoxic agents. Hypokalaemia can precipitate the long QT syndrome, as well as potentially lethal ventricular arrhythmias like torsade de pointes. Synergism is likely to occur when either QT interval-modifying drugs (e.g. terfenadine and astemizole) and drugs that induce hypokalaemia (e.g. amphotericin B) are coadministered. Induction and inhibition of cytochrome P450 enzymes at hepatic and extrahepatic sites are the mechanisms that underlie the most serious pharmacokinetic drug interactions of the azole antifungals. These agents have been shown to notably decrease the catabolism of numerous drugs: histamine H1 receptor antagonists, warfarin, cyclosporin, tacrolimus, digoxin, felodipine, lovastatin, midazolam, triazolam, methylprednisolone, glibenclamide (glyburide), phenytoin, rifabutin, ritonavir, saquinavir, nevirapine and nortriptyline. Non-antifungal drugs like carbamazepine, phenobarbital (phenobarbitone), phenytoin and rifampicin (rifampin) can induce the metabolism of azole antifungals. The bioavailability of ketoconazole and itraconazole is also reduced by drugs that increase gastric pH, such as H2 receptor antagonists, proton pump inhibitors, sucralfate and didanosine. Griseofulvin is an enzymatic inducer of coumarin-like drugs and estrogens, whereas terbinafine seems to have a low potential for drug interactions. Despite important advances in our understanding of the mechanisms underlying pharmacokinetic drug interactions during the 1990s, at this time they still remain difficult to predict in terms of magnitude in individual patients. This is because of the large interindividual and intraindividual variations in the catalytic activity of those metabolising enzymes that can either be induced or inhibited by various drugs. Notwithstanding these variations, increasing clinical experience is allowing pharmacokinetic interactions to be used to advantage in order to improve the tolerability of some drugs, as recently exemplified by the use of a fixed combination of ketoconazole and cyclosporin.     

Multiple infection with Toxocara canis. Influence of antihistamines and corticosteroids on the histopathological response

The histopathology of the tissues of mice infected with ten doses of 100 embryonated eggs of Toxocara canis and the influence of antihistamines and corticosteroids on these findings is described. The main lesions were confined to the liver and lungs. In infected but untreated control mice hepatic lesions consisted of periportal infiltrates, widespread foci of liver cell necrosis and polymorphonuclear and mononuclear accumulation and a few fibrotic granulomata. Treatment with antihistamines did not change these findings significantly, but corticosteroids decreased the amount of cellular infiltration and the size of the lesions. Pulmonary lesions consisted mostly of confluent infiltrates of polymorphonuclears, eosinophils and mononuclear cells with some macrophage proliferation. Neither drug seemed to affect the lung involvement.     

Oral antihistamines reduce the side effects from rapid vancomycin infusion

Recombinant human mu-calpain whose active site Cys-115 was substituted with Ser was expressed in insect cells using baculovirus system. The mutant mu-calpain, purified using an affinity-column of calpastatin oligopeptides, had no proteolytic activities of autolysis and caseinolysis. The large subunit of the mutant mu-calpain was processed from the 80 kDa form to the 76 kDa form by the wild type calpain, supporting the intermolecular cleavage mechanism of procalpain during activation. Fluorescence polarization analysis revealed that the mutant mu-calpain retained high affinity toward fluorescein-labeled calpastatin domain 1. Fragmentation of the full-length calpastatin by the wild type calpain was enhanced by pre-incubating the inhibitor with the mutant calpain. The recombinant mutant calpain was suggested to retain the integrity of the high ordered structure of the wild type calpain.     

Drug interactions in the horse: effect of furosemide on plasma and urinary levels of phenylbutazone

Horses pretreated with 6.6 mg/kg of phenylbutazone were injected with 1 mg/kg of furosemide intravenously. Furosemide had no clinically significant effect on either plasma levels or plasma half-life of phenylbutazone. Furosemide reduced urinary levels of phenylbutazone 18-fold to concentrations which may result in inconsistent drug detection in routine screening tests. The results show that it is not possible to monitor compliance with phenylbutazone medication rules by means of urinalysis alone if the use of furosemide is permitted. Furosemide treatment, however, does not interfere with monitoring by plasma level determinations.     

Guanidines as analogs of histamine and antihistamines on the isolated guinea-pig ileum

The present work describes the interaction of phenylguanidine and cyclohexylguanidine with receptor structures of the isolated guinea-pig ileum. It is suggested that phenylguanidine in the range of 0.2-2 mM, acts in a way similar to histamine. At lower concentrations in the bath, phenylguanidine and cyclohexylguanidine, behave as competitive antagonists of histamine, with Ki values close to 0.1 mM and 0.4 mM, respectively. At higher concentrations phenylguanidine acts as agonist with a Kn near 0.3 mM; the Kn for histamine was found to be 0.127 muM, in agreement with previous data from the literature. The agonistic action of phenylguanidine is inhibited by promethazine and atropine, which have Ki values of 0.342 muM and 0.575 muM, respectively. Cyclohexylguanidine is devoid of spasmogenic activity, and this was attributed to the lack of aromatic character and to the bulkiness of the cyclohexyl side chain.