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 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.     

Influence of grapefruit juice on caffeine pharmacokinetics and pharmacodynamics

The influence of grapefruit juice (GFJ) on caffeine's metabolism and the hemodynamic effects of this potential food interaction were studied in 10 normotensive volunteers. In this crossover study, caffeine (3.3 mg/kg) and water or caffeine and GFJ were given to participants. Nine serum caffeine concentrations were determined within 24 hours of each phase. In another phase of this study, caffeine was given with multiple GFJ doses to 6 of the 10 participants. Ambulatory blood pressure (BP) monitors were used for 12 hours to assess treatment hemodynamic effects. The mean area under the serum caffeine concentration-time curve (AUC0-infinity) values +/- SD for the caffeine with water group, caffeine with GFJ group, and caffeine with multiple GFJ group were 47.0 +/- 10.8, 48.7 +/- 15.2, and 49.6 +/- 7.0 micrograms/ml.hr, respectively (NS). There was no significant difference on the ambulatory systolic BP, diastolic BP, percentage of the time with a diastolic BP greater than 90 mm Hg, or heart rate area under the effect curves. We conclude that grapefruit juice had no effect on caffeine pharmacokinetics or hemodynamic effects.     

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.     

Grape juice but not orange or grapefruit juice inhibits platelet activity in dogs and monkeys

Platelet aggregation (PA) contributes to both the development of atherosclerosis and acute platelet thrombus formation (APTF) followed by embolization producing cyclic flow reductions (CFR) in stenosed and damaged dog and human coronary arteries. In seven anesthetized dogs with coronary stenosis and medial damage, CFR occurred at 7 +/- 3/30 min and were abolished 127 +/- 18 min after gastric administration of 10 mL of purple grape juice/kg. Collagen-induced ex vivo whole blood PA decreased by 49 +/- 9% after the abolishment of CFR with grape juice. Ten mL of orange juice/kg (n = 5) and 10 mL of grapefruit juice/kg (n = 5) had no significant effect on the frequency of the CFR or on ex vivo PA. In vitro studies have suggested that flavonoids bind to platelet cell membranes and thus may have an accumulative or tissue-loading effect over time. To test this we fed 5 mL of grape juice/kg to 5 cynomologous monkeys for 7 d. Collagen-induced ex vivo PA decreased by 41 +/- 17% compared to control (pre-reatment) after 7 d of feeding. In the same 5 monkeys, neither 5 mL of orange juice/kg nor 5 mL of grapefruit juice/kg given orally for 7 d produced any significant change in PA. Grape juice contains the flavonoids quercetin, kaempferol and myricetin, which are known inhibitors of PA in vitro. Orange juice and grapefruit juice, while containing less quercetin than grape juice, primarily contain the flavonoids naringin, luteolin and apigenin glucoside. The flavonoids in grapes were shown in vitro to be good inhibitors of PA, whereas the flavonoids in oranges and grapefruit to be poor inhibitors of PA. The consumption of grape juice, containing these inhibitors of PA, may have some of the protection offered by red wine against the development of coronary artery disease (CAD) and acute occlusive thrombosis, whereas orange juice or grapefruit juice may be ineffective. Thus, grape juice may be a useful alternative dietary supplement to red wine without the concomitant alcohol intake.     

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.     

Clinical relevance of drug interactions with lithium

Although lithium continues to be regarded as the treatment of choice for bipolar disorders, the clinical use of this mood stabiliser is associated with an extremely narrow therapeutic range. Relatively minor increases in serum concentrations may induce serious adverse sequelae, and concentrations within the therapeutic range may result in toxic reactions. The safety of combining lithium with other medications, therefore, is a major concern, and extensive clinical experience has served to identify several significant drug interactions. Lithium removal from the body is achieved almost exclusively via renal means. As a result, any medication that alters glomerular filtration rates or affects electrolyte exchange in the nephron may influence the pharmacokinetic disposition of lithium. Concomitant use of diuretics has long been associated with the development of lithium toxicity, but the risk of significant interactions varies with the site of pharmacological action of the diuretic in the renal tubule. Thiazide diuretics have demonstrated the greatest potential to increase lithium concentrations, with a 25 to 40% increase in concentrations often evident after initiation of therapy. Osmotic diuretics and methyl xanthines appear to have the opposite effect on lithium clearance and have been advocated historically as antidotes for lithium toxicity. Loop diuretics and potassium-sparing agents have minor variable effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been associated with lithium toxicity, although the relative interactive potential of specific NSAIDs is difficult to determine. Small prospective studies have demonstrated large interindividual differences in lithium clearance values associated with different NSAIDs. A growing body of evidence also suggests that ACE inhibitors may impair lithium elimination, but further investigations are needed to identify patients at risk. Anecdotal reports have linked numerous medications with the development of neurotoxicity without an apparent effect on the pharmacokinetic disposition of lithium. Antipsychotics, anticonvulsants and calcium antagonists have all be implicated in a sufficient number of case reports to warrant concern. As these medications have all been commonly coadministered with lithium, the relative risk of serious interactions appears to be quite low, but caution is advised.     

Antimicrobial resistance in staphylococci. Epidemiology, molecular mechanisms, and clinical relevance

Staphylococcal infections continue to pose important clinical problems in children and adults. Antibiotic resistance among the staphylococci has rendered therapy of these infections a therapeutic challenge. Despite early, uniform susceptibility to penicillin, staphylococci acquired a gene elaborating beta-lactamase that rendered penicillin inactive and that is borne by nearly all clinical isolates. "Penicillinase-resistant beta-lactams," such as methicillin, were introduced in the early 1960s, but resistance to them has become an increasing concern. The mechanism of the so-called "methicillin resistance" is complex. Moreover, once confined to the ecology of hospitals and other institutions, a recent increase in community-acquired methicillin-resistant S. aureus infections has been observed. Glycopeptides, until now the only uniformly reliable therapeutic modality, have been increasingly used for therapy of staphylococcal infections. The recent recognition of clinical isolates with reduced susceptibility to glycopeptides is of concern.     

Drug interactions with the nonsedating antihistamines

The nonsedating antihistamines are frequently prescribed agents. Well-documented drug-drug interactions with two of these agents, terfenadine and astemizole, may result in serious adverse effects, including death, when they are prescribed along with macrolide antibiotics and/or the antifungal agents itraconazole or ketoconazole. Fexofenadine and loratadine appear to be the least likely nonsedating antihistamines to interact with other medications and to result in a life-threatening interaction. This article reviews the known drug-drug interactions involving nonsedating antihistamines and provides a basis from which the clinician can predict potential interactions.     

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.     

Grapefruit juice-terfenadine single-dose interaction: magnitude, mechanism, and relevance

Effective management of human health and ecological hazards in the manufacturing and maintenance environment can be achieved by focusing on the risks associated with these operations. The NDCEE Industrial Health Risk Assessment (IHRA) Program is developing a comprehensive approach to risk analysis applied to existing processes and used to evaluate alternatives. The IHRA Risk-Based Tiered Approach (RBTASM) builds on the American Society for Testing and Materials (ASTM) Risk-Based Corrective Action (RBCA) effort to remediate underground storage tanks. Using readily available information, a semi-quantitative ranking of alternatives based on environmental, safety, and occupational health criteria was produced. A Rapid Screening Assessment of alternative corrosion protection products was performed on behalf of the Joint Group on Acquisition Pollution Prevention (JG-APP). Using the RBTASM in pollution prevention alternative selection required higher tiered analysis and more detailed assessment of human health risks under site-specific conditions. This example illustrates the RBTASM for a organic finishing line using three different products (one conventional spray and two alternative powder coats). The human health risk information developed using the RBTASM is considered along with product performance, regulatory, and cost information by risk managers downselecting alternatives for implementation or further analysis.     

The clinical relevance of reduced sensory stimulation.

Reviews theoretical and empirical connections between psychopathology, therapy, and reduced sensory stimulation. Decreases in sensory and social stimulation have been found to cause or aggravate psychological as well as physical dysfunctions in a wide variety of contexts. Such deprivation in infancy may lead to irreversible damage, while even brief periods of deprivation in adulthood have effects which, although temporary, are quite dramatic. At the same time, there is evidence that sensory deprivation is a promising therapeutic method or adjunct to other methods. (172 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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.     

Online tools for evaluating patient change: Statistical foundations, clinical applications, research relevance.

Purpose: To present Internet-based tools for evaluating whether meaningful change has occurred in individual patients across time. These tools were developed to make empirically based analyses of clinical change readily available to clinicians and clinical researchers. Method: Tools were developed on the basis of 4 statistical paradigms, including (a) the Reliable Change Index, (b) the Reliable Change Index with an adjustment for bias, (c) bivariate regression, and (d) multivariate regression. A library of measures that uses these platforms is described. Conclusions/Implications: Clinical indications and limitations for using these tools are explained. Clinical reasoning involved in using these tools is discussed and demonstrated with case illustrations. The clinical and research potential of these tools is discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Apoptosis: clinical relevance and pharmacological manipulation

Apoptosis, often synonymously used with the term 'programmed cell death', is an active, genetically controlled process that removes unwanted or damaged cells. Suppression, overexpression or mutation of a number of genes which orchestrate the apoptotic process are associated with disease. The diseases in which apoptosis has been implicated can be grouped into 2 broad groups: those in which there is increased cell survival (i.e. associated with inhibition of apoptosis) and those in which there is excess cell death (where apoptosis is overactive). Diseases in which there is an excessive accumulation of cells include cancer, autoimmune disorders and viral infections. Deprivation of trophic factors is known to induce apoptosis in cells dependent on them for survival. This fact has been exploited in the use of antiandrogens or antiestrogens in the management of prostate or breast cancer. Haemopoietic growth factors like granulocyte-macrophage colony stimulating factor (GM-CSF) or interleukin-3 prevent apoptosis in target cells and modulation of levels of these factors has been tried in the prevention of chemotherapy-induced myelosuppression. Until recently, it was thought that cytotoxic drugs killed target cells directly by interfering with some life-maintaining function. However, of late, it has been shown that exposure to several cytotoxic drugs with disparate mechanisms of action induces apoptosis in both malignant and normal cells. Physiological regulation of cell death is essential for the removal of potentially autoreactive lymphocytes during development and the removal of excess cells after the completion of an immune response. Recent work has clearly demonstrated that dysregulation of apoptosis may underlie the pathogenesis of autoimmune diseases by allowing abnormal autoreactive lymphocytes to survive. AIDS and neurodegenerative disorders like Alzheimer's or Parkinson's disease represent the most widely studied group of disorders where an excess of apoptosis has been implicated. Amyotrophic lateral sclerosis, retinitis pigmentosa, epilepsy and alcoholic brain damage are other neurological disorders in which apoptosis has been implicated. Apoptosis has been reported to occur in conditions characterised by ischaemia, e.g. myocardial infarction and stroke. The liver is a site where apoptosis occurs normally. This process has also been implicated in a number of liver disorders including obstructive jaundice. Hepatic damage due to toxins and drugs is also associated with apoptosis in hepatocytes. Apoptosis has also been identified as a key phenomenon in some diseases of the kidney, i.e. polycystic kidney, as well as in disorders of the pancreas like alcohol-induced pancreatitis and diabetes.