Severe Drug Interactions Research Articles

Development and evaluation of an individuals-oriented information-provision system for outpatients--utility of "drug Usage sheets" and "Drug Information Cards" for patient consultation

We have implemented an information-provision system for outpatients at the department of pharmacy, University of Tokyo Hospital, in order to comply with the revised Pharmacists' Law by which pharmacists have been obliged to provide patients with information necessary for rational usage of medicine at the time they receive dispensed drugs. This system is linked on-line with the order entry system to print "Drug Usage Sheets" containing important drug information such as therapeutic effects and adverse reactions, as well as photographic color views of drugs. We prepared the sheets by extracting and classifying the original information, and by converting medical terms into lay expressions. Moreover, we developed "Drug Information Cards" to inform each patient of severe side effects and drug interactions, which should affect drug compliance, and implemented an individuals-oriented information system using both the "Drug Usage Sheets" and "Drug Information Cards." In this study, we evaluated the usefulness of this system from the viewpoint of patients' recognition and understanding on necessary drug information. It was indicated from questionnaires to patients that the "Drug Usage Sheets" help most patients understand the names, usage, effects, and general cautions including slight adverse reactions (i.e. grade 1), and that the use of colored letters for important parts and pictograms is a useful method to attract more attention from patients as compared with a conventional method using only letters. Most patients answered that the "Drug Usage Sheets" can be utilized in many ways and valuable in taking drugs with assurance. We formulated the "Drug Information Cards" by information processing: separation of early symptoms of adverse effects into subjective and objective ones and their classification into related organs. Moreover, the brand names of drugs which may cause drug interactions have been listed on the cards so that worsening of adverse reactions and drug interactions can be avoided. Although 14% of the patients answered that they became unsecured when informed on side effects, the percentage of such patients was significantly higher with those who received caution-required drugs for the first time or who have experienced drug side effects before, suggesting the need for combining oral explanation based on each patient's background and understanding on drug adverse effects. In conclusion, an efficient provision of drug information became possible through our integration of necessary drug information in this study, and the individuals-oriented system of drug information was established, which was demonstrated to contribute to the rational usage of medicine.

Differential kinetics of phenytoin in elderly patients.

The elderly have a relatively high risk of developing adverse drug reactions. Phenytoin continues to be a preferred drug for treating generalised tonic-clonic seizures in the elderly and simple partial seizures that generalise. Phenytoin is eliminated almost entirely by hepatic oxidation. The principle enzymes responsible are cytochrome P450 (CYP)2C9 and CYP2C19. CYP2C9 is saturated by therapeutic doses of phenytoin, and at steady state both enzymes are probably operant in most people. The nonlinear pharmacokinetics of phenytoin make it a difficult drug for which to establish safe and effective administration regimens. An important area of inquiry is whether the differential disposition kinetics of phenytoin in the elderly render its administration an even more difficult challenge. Moreover, since the elderly are generally subject to more polypharmacy than younger adults, are they, as a result, subject to either more frequent or more severe drug interactions with phenytoin than younger adults? In order to examine these issues we were interested in learning the extent to which old age might affect the plasma protein binding of phenytoin, its hepatic metabolism and, ultimately, its pharmacokinetic profile. With regard to the latter we looked carefully at the methods that have been used to characterise the disposition kinetics of phenytoin in general, and in the elderly, in particular. There are many conflicting findings with regard to the effect of age on the disposition kinetics of phenytoin. However, the strategies used for estimating kinetic parameters for phenytoin [viz the maximum rate of metabolism/elimination (Vmax) and the Michaelis-Menton constant (Km)] exhibit deficiencies that could account for some of the disparate findings. Certainly, more careful prospective studies focusing on the effects of age on phenytoin disposition kinetics are warranted. However, in light of the information currently available, no special attention need be paid to the initiation of phenytoin administration in elderly patients who are taking multiple anticonvulsants. On the other hand, for the elderly receiving phenytoin monotherapy, the initiation of phenytoin administration should occur at lower doses than would be customary for younger adults, and phenytoin blood concentrations should be appropriately monitored in order to evaluate individual Vmax and Km values for informed dosage adjustments.

Drug interactions of HIV protease inhibitors.

All the currently available protease inhibitors are metabolised by the cytochrome P450 (CYP) enzyme system. All are inhibitors of CYP3A4, ranging from weak inhibition for saquinavir to very potent inhibition for ritonavir. Thus, they are predicted to have numerous drug interactions, although few such interactions have actually been documented either in pharmacokinetic studies or in clinical reports. This article reviews the published literature with an emphasis on the magnitude of interactions and on practical recommendations for management. Many of the drugs commonly taken by patients with HIV have a strong potential to interact with the protease inhibitors. In particular, the non-nucleoside reverse transcriptase inhibitors are also metabolised by CYPand have been shown to interact with protease inhibitors. Delaviridine is an inhibitor of CYP3A4, but nevirapine and efavirenz are inducers of CYP3A4. The protease inhibitors also interact with each other, and these interactions are being explored for their potential therapeutic benefits. Other commonly used drugs are also known to affect protease inhibitor metabolism, including inhibitors such as clarithromycin and the azole antifungals and inducers such as the rifamycins. Drugs that are known to be significantly affected by the protease inhibitors include ethinylestradiol and terfenadine; many other drugs have lesser or potential interactions. Although little specific data is available on the drug interactions of protease inhibitors, this lack of data should not be interpreted as a lack of interaction. Retrospective chart reviews have demonstrated that potentially severe drug interactions are frequently overlooked. Much more clinical data is needed, but pharmacists and physicians must always be vigilant for drug interactions, both those that are already documented and those that are predictable from pharmacokinetic profiles, in patients receiving protease inhibitors.

Nontuberculous mycobacteria.

The nontuberculous mycobacteria (NTM), especially Mycobacterium avium complex, are being recognized with increasing frequency as clinical pathogens, not only as a cause of disseminated disease in patients with AIDS but also as a cause of chronic lung disease in patients without AIDS. These infections have traditionally been difficult and frustrating to treat; however, the introduction of new agents, such as clarithromycin, azithromycin, and rifabutin, has significantly improved outcome for patients with some NTM infections. The new therapeutic regimens can be associated with severe toxicities and drug interactions that dictate the need for careful monitoring of patients undergoing treatment for M. avium complex disease. Clinicians will be called on with increasing frequency to determine the significance of NTM isolated from their patients. This determination will require knowledge about the pathogenicity and the appropriate therapy of a variety of NTM species.

Risk-Benefit Assessment of Newer Versus Older Monoamine Oxidase (MAO) Inhibitors

The first generation of monoamine oxidase (MAO) inhibitors fell into disuse because of poor efficacy in major depression with melancholia and/or endogenous depression, and because of poor tolerability (drug interactions and the 'cheese' effect). New MAO inhibitors, reversible inhibitors of MAO-A (RIMAs), are able to induce a reversible and specific inhibition of MAO-A. Consequently, the inhibition of MAO is quicker and the dose-response relationship improved, such that dosage adjustment is easier. Also, no carry-over effect once treatment is terminated is observed. The frequency and severity of drug interactions with RIMAs is reduced, although coadministration with pethidine (meperidine) or dextromethorphan should still be avoided. No specific subgroup of patients with depression has shown a better or worse response to RIMAs. The presence of melancholia in major depression, or the existence of endogenous depression, are not predictive of reduced efficacy compared with tricyclic antidepressant (TCA) reference compounds. Dysthymic patients have shown a good response to both RIMAs and TCAs independent of the co-existence of a major depressive episode. Older MAO inhibitors are more effective than TCAs in the treatment of atypical depression, and further studies are needed to confirm if this is true for RIMAs. Long term studies to evaluate the effects of RIMAs on disease recurrence are also required. RIMAs are better tolerated than older MAO inhibitors, including use in subgroups particularly at risk of adverse effects such as the elderly. Overall, RIMAs appear to represent therapeutic progress in the treatment of depression in terms of both efficacy and tolerability.

Adverse Effects and Drug Interactions of Clinical Importance with Antiviral Drugs

Most antiviral drugs are nucleoside analogues with potential teratogenic, embryotoxic, carcinogenic and antiproliferative activities. They must be administered with caution during pregnancy, because some are known teratogens (e.g. amantadine) and a similar propensity cannot be entirely excluded for others (e.g. aciclovir). Their adverse effects mostly involve bone marrow depression (e.g. granulocytopenia with ganciclovir, anaemia with zidovudine) or neurotoxicity (e.g. seizures with interferon-alpha, peripheral neuropathy with zalcitabine), although gastrointestinal effects are also seen. Idiosyncratic reactions include didanosine-induced acute pancreatitis. Only inosine pranobex is largely free from toxicity. Idoxuridine must be administered topically, given the severity of its systemic adverse effects. Drug interactions involving antiviral agents mostly reflect shared toxicity with other agents (e.g. neutropenia with ganciclovir and zidovudine, pancreatitis with didanosine and alcohol), although renal excretion or hepatic metabolism may be implicated. Given the possibility of severe adverse reactions and drug interactions, antiviral chemotherapy should only be used for potentially serious virus infections. Topical administration avoids systemic adverse effects but not mutagenic risks, and may result in exposure of individuals other than the patient (e.g. aerosolised ribavirin).

Pharmacokinetic drug interactions of macrolides.

The macrolide antibiotics include natural members, prodrugs and semisynthetic derivatives. These drugs are indicated in a variety of infections and are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions. Macrolides can both inhibit drug metabolism in the liver by complex formation and inactivation of microsomal drug oxidising enzymes and also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 years, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard and not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes and the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin and midecamycin) form complexes to a lesser extent and rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin and azithromycin) do not inactivate cytochrome P450 and are unable to modify the pharmacokinetics of other compounds. It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 and the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group and the hydrophobic character of the drug. Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decrease of the metabolism of methylprednisolone, theophylline, carbamazepine, phenazone (antipyrine) and triazolam. Troleandomycin can cause ergotism in patients receiving ergot alkaloids and cholestatic jaundice in those taking oral contraceptives. Erythromycin and its different prodrugs appear to be less potent inhibitors of drug metabolism. Case reports and controlled studies have, however, shown that erythromycins may interact with theophylline, carbamazepine, methylprednisolone, warfarin, cyclosporin, triazolam, midazolam, alfentanil, disopyramide and bromocriptine, decreasing drug clearance. The bioavailability of digoxin appears also to be increased by erythromycin in patients excreting high amounts of reduced digoxin metabolites, probably due to destruction of enteric flora responsible for the formation of these compounds. These incriminated macrolide antibiotics should not be administered concomitantly with other drugs known to be affected metabolically by them, or at the very least, combined administration should be carried out only with careful patient monitoring.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacology of Drugs for Conscious Sedation

In endoscopic monitoring and treatment of gastrointestinal disease, it is important that patients will accept repeated examination. They are less likely to do so if the procedure is remembered as distressing or uncomfortable, as is likely when it is performed under topical anaesthesia alone. The aim of conscious sedation is a lightly sedated patient, who is awake, cooperative on demand, amnesic, and free from anxiety and fear. Various drugs in low doses can be used to meet these criteria. Among these are phenothiazines, butyrophenones, barbiturate and non-barbiturate hypnotics, benzodiazepines, and the hypno-analgesic, ketamine. As benzodiazepines offer both sedative and profound amnesic and anxiolytic effects, these drugs are used for conscious sedation worldwide. Diazepam has been the 'gold standard' of sedation, but the more modern benzodiazepines, particularly midazolam, are now more commonly used. In general, benzodiazepines demonstrate a broad therapeutic range. In accordance with dose, however, sedative drugs may induce side-effects, such as drowsiness, lowering of blood pressure, and respiratory depression. In addition, some may induce more wide-ranging side-effects, such as histamine liberation and anaphylactic reactions, thrombophlebitis, and pain on injection. They may have severe drug interactions when used in combination with local anaesthetics, hypnotics and opioids. In older patients, lower doses are necessary for sedation. Sedative drugs should be administered slowly, to avoid haemodynamic and respiratory side-effects.

Drug Interactions in Perspective

Selected classes of medication are presented, and the frequently occurring and/or severe drug interactions common to these agents are reviewed. Selected tables are presented, for immediate reference, but the reader is referred to the standard drug interaction compendia for routine reference. The responsibility of the pharmacist for monitoring and preventing patient injury from interactions is emphasized.

Interaction of Cationic Drugs with Nafion on Electrode Surfaces and Its Applicability to Determination of Electroinactive Drugs

Abstract The interaction of several electroinactive cationic drugs (hexamethonium, quinidine, neostigmine, nicotine and acetylcholine) with Nafion and the applicability of Nafion-coated electrodes to determination of the drugs have been investigated. The addition of a drug to an electrolyte solution containing (ferrocenylmethyl)trimethylammonium (FA+) induced a decrease in the peak current and a shift in the apparent half-wave potential of a cyclic voltammogram for FA+. The decrease in the peak current has been used for determination of the drugs at low concentrations less than 10−3 mol dm−3. The ion-selectivity coefficients of Nafion for the drugs have been determined by an electrochemical method. These drugs showed quite large values and the values seemed to be dependent on the hydrophobicity of the drugs.

Drug Interactions and Incompatibilities

The clinical significance of drug interactions in animals is often minor, but, in some cases, they may result in a fatal outcome. In the critically ill patient, the temptation to employ relatively large doses, particularly of antimicrobials or corticosteroids, or to use multiple-drug therapy is enhanced. These two factors, combined with a debilitated state of the patient, increase the probability of severe drug interactions that could mean the difference between recovery or death. It would be prudent to consider the possibility of drug interactions when selecting drugs for concomitant use, evaluating adverse reactions, evaluating laboratory test results, or mixing drugs in vitro.

Influence of the antitumour antibiotics daunomycin and violamycin B I on membranes of human erythrocytes: Passive electrical investigations

The interaction of several anthracycline antitumour drugs with human erythrocytes was investigated by passive electrical measurements. The results show that mainly the cell membrane capacity is changed after addition of violamycin B I, while daunomycin used in chemotherapy affects the conductivity inside the red blood cells significantly. An attempt was made to find a correlation between the observed changes of the electrical parameters and the chemical structures of these drugs.

Comparison of the muscarinic cholinoceptors in the rabbit ciliary body and the guinea-pig ileum

Interactions of several muscarinic drugs with their receptors were studied in the ciliary body smooth muscle of rabbits and the ileal longitudinal muscle of guinea-pigs, using pharmacological and biochemical procedures. The dissociation constants of carbachol, pilocarpine, atropine and pirenzepine estimated by these procedures indicate no heterogeneity of muscarinic receptors in either tissue; thus both are probably of the M 2 type. However, the density of the receptors in the ciliary body is lower than in the ileum. Pilocarpine, with lower intrinsic efficacy, demonstrated a pronounced organ selectivity when compared to carbachol as it was a potent full agonist in the ileum and a competitive antagonist in the ciliary body. These results suggest the importance of both receptor density and threshold as determinants of agonist potency.

Interaction of several drugs with Tyr 411 anthraniloyl human serum albumin.

In order to establish the contribution of Tyr 411 of human serum album in (HSA) to specific drug binding, the effect to drug binding on the fluorescence spectrum of HSA in which Tyr 411 was modified with p-nitrophenyl anthranilate (ANT-HSA) was studied by using various drugs (diazepam, chlordiazepoxide, fluenamic acid, indomethacin, azapropazone, phenylbutazone, warfarin, salcylic acid, ibuprofen, L-tryptophan, tolbutamide and sulfadimethoxine). Among these durugs, indomethacin and flufenamic acid strongly quenched the fluorescence of the anthraniloyl group of ANT-HSA at a molar ratio of 1.0, indicating that these drugs bind near the Tyr 411 residue.

Muscarinic Acetylcholine Receptors in the Rabbit Ciliary Body Smooth Muscle: Spare Receptors and Threshold Phenomenon

Interactions of several muscarinic drugs with their receptors were studied in the ciliary body smooth muscles of the rabbit. The ciliary body smooth muscles responded to carbachol, a muscarinic full agonist with concentration-dependent contractions, and the pD2 value of carbachol was 5.16±0.05. Atropine, a competitive antagonist of muscarinic receptors, produced a parallel shift to the right in the concentration-response curves for carbachol. Pilocarpine which is a well-known partial agonist on muscarinic receptors in most smooth muscles did not cause any contraction in this tissue. The drug, however, behaved as a competitive antagonist on the muscarinic receptors in the ciliary body smooth muscles. The pA2 values of atropine and pilocarpine versus carbachol obtained from the Schild plot are 8.97±0.25 and 5.17±0.09, respectively. On the other hand, arecoline and oxotremorine acted as a partial agonist in this tissue. The intrinsic activity, and pD2 and pA2 values were 0.41 ±0.02, 4.93±0.05 and 5.32±0.05 for arecoline respectively, and were 0.26±0.02, 5.64±0.08 and 6.12±0.16 for oxotremorine, respectively. The pA2 values of these drugs were significantly larger than the corresponding pD2 values of the drugs. The values of the negative log molar dissociation constant of carbachol, arecoline and oxotremorine estimated by the method of partial irreversible blockade of spare receptors with 3x10“6 M phenoxybenzamine were 4.53±0.08, 5.20±0.09 and 6.02±0.06, respectively. These values were practically equal to those obtained from other peripheral tissues, suggesting that the muscarinic receptors in rabbit ciliary body smooth muscles were qualitatively the same as those of other smooth muscles. However, the density of muscarinic receptors in this tissue is lower than that in other peripheral tissues, and the threshold phenomenon lay between the occupation of muscarinic receptors and the tissue responses. Therefore, the pA2 values of partial agonists were different from their pD2 values, and pilocarpine, a partial agonist with lower intrinsic efficacy, behaved as a competitive antagonist in this tissue. These results suggest the importance of the receptor density and the threshold in the tissue as well as the affinity and the intrinsic efficacy of the drug as a determinant of agonist potency.

Immunomodulating agents and hepatic drug-metabolizing enzymes.

Immunomodulating agents are increasingly used in clinical practice to alter the course of various malignancies, autoimmune diseases, or immunodeficiencies. Experimental data obtained in laboratory animals suggest that nearly all agents available today are likely to inhibit hepatic drug-metabolizing enzymes. Although further investigation is warranted, a direct stimulation of the reticuloendothelial system is likely to play a key role. Potentially severe drug interactions are the main clinical consequences to be considered, particularly in the field of cancer chemoimmunotherapy and vaccination. Besides immunomodulating agents, drugs with the toxic potential for immunoenhancement may also be considered in that respect.

Studies on nitrosamine formation by the interaction between drugs and nitrite. II. Hepatotoxicity by the simultaneous administration of several drugs and nitrite.

The alterations of biochemical parameters, namely, glutamic oxaloacetic transaminase and glutamic pyruvic transaminase in serum, hepatic microsomal drug oxidation systems, glucose-6-phosphate dehydrogenase and lysozomal enzymes in hepatic soluble fraction were investigated for the purpose of semiquantitatively estimating the hepatotoxicity caused by the interaction of several drugs and sodium nitrite in rats. The simultaneous administration of aminopyrine and sodium nitrite induced the alterations of these parameters. However, these alterations were not induced by the administration of antipyrine and sodium nitrite. Therefore the alterations were thought to be mainly due to N-nitrosodimethylamine formed. The administration of 0.4 mmole/kg of aminopyrine and 1.0 mmole/kg of sodium nitrite was thought to induce the alterations to almost the same extent as induced by 0.15 mmole/kg of N-nitrosodimethylamine. The simultaneous administrations of sodium nitrite and several other drugs with tertiary amino groups, namely oxytetracycline, diphenhydramine, oleandomycin, erythromycin and minocycline induced small alterations of these parameters. However, these alterations were not thought to relate to the hepatic injury induced by N-nitrosodimethylamine. Therefore the amount of N-nitrosodimethylamine formed from these drugs in rats was thought to be rather small. We also investigated the effect of several antioxidants on the alterations of biochemical parameters induced by aminopyrine and sodium nitrite. Ascorbic acid, sodium erythorbate and propyl gallate inhibited these alterations. On the other hand, sorbic acid did not.

Studies on nitrosamine formation by the interaction between drugs and nitrite. I. Measurement of the amount of nitrosamine formed in rat and guinea pig stomachs.

The amounts of nitrosamine formed by the interaction of several drugs and nitrite in rat and guinea pig stomachs were estimated. The nitrosamine formation from aminopyrine and nitrite was much more in guinea pig stomachs than in rat stomachs. It seemed that this result was due to the difference in gastric contents of these animals. As the nitrosamine formation was also indicated in the interaction of a clinically prescribed dose of aminopyrine and very low doses of nitrite in rat and guinea pig stomachs, there is a possibility that the nitrosation of aminopyrine takes place in human stomachs, too. Minocycline also interacted with nitrite and formed N-nitrosodimethylamine. However, the amount of nitrosamine formed was less in minocycline than in aminopyrine. Oxytetracycline was not found to form nitrosamine in the stomachs of these animals. The effects of several compounds on the nitrosamine formation by the interaction of aminopyrine and nitrite were also investigated. Ascorbic acid, sodium erythorbate, propyl gallate and butylated hydroxyanisole reduced the nitrosamine formation but the effect of alpha tocopherol, sorbic acid and butylated hydroxytoluene was not observed in the stomach.

Interaction of several nonsteroidal antiinflammatory drugs with pectin in aqueous solution and in solid state.

Interaction between several nonsteroidal antiinflammatory drugs and pectin was studied by the centrifugation method, the equilibrium dialysis method and the solubility method. Benzydamine hydrochloride (BZM) and ketoprofen (KPF) formed coprecipitates with pectin by the centrifugation method, and the binding isotherms of BZM and pectin showed a multi-layer type. On the other hand, the binding isotherm of BZM to pectin by the equilibrium dialysis method showed a Langmuir type in low equilibrium concentration range and the saturated amount bound decreased with an increase of ion concentration of the solution. The solubility of all drugs used decreased with an increase of concentration of pectin. IR absorption spectroscopy, X-ray diffraction pattern and differential scanning calorimetry of the BZN/pectin coprecipitate showed clear difference from the physical mixture. The dissolution rate of BZM/pectin coprecipitate and physical mixture of BZM and pectin was very slow in comparison with intact BZM and physical mixture of BZM and galacturonic acid. Pectin forms water insoluble complexes with these nonsteroidal antiinflammatory drugs, suggesting a usefulness as an additive for sustained-release preparations, and this might afford a mean for reducing adverse reactions of nonsteroidal antiinflammatory drugs to stomach after oral administration.

Benzodiazepine receptor binding: the interactions of some non-benzodiazepine drugs with specific [3H] diazepam binding to rat brain synaptosomal membranes.

The interaction of several non-benzodiazepine drugs with [3H] diazepam binding to benzodiazepine receptors in rat brain synaptosomal membranes was investigated. Baclofen, benzoctamine, hydroxyzine, chlorpromazine, haloperidol, imipramine, and amitriptyline displace specific [3H] diazepam binding, but the concentrations needed are too high to explain pharmacological effects of these drugs by an interaction with benzodiazepine receptors. The most potent non-benzodiazepine drug for inhibiting specific [3H] diazepam binding was methaqualone (IC50 value of 150 micrometer). It is suggested that interactions with benzodiazepine receptors may account for the anxiolytic and anticonvulsive side effects of this drug. The analeptic drug pentylenetetrazole interacts with benzodiazepine receptor binding with an IC50 value of about 1 mM, which is possibly too high to explain its convulsive properties by an antagonism at the benzodiazepine receptor.