Pharmacological importance of stereochemical resolution of enantiomeric drugs

Drug enantiomers have identical properties in an achiral environment, but should be considered as different chemical compounds. This is because they often differ considerably in potency, pharmacological activity and pharmacokinetic profile, since the modules with which they interact in biological systems are also optically active. Within biological systems, the metabolism of one isomer may be via a different pathway or occur at a different rate from that of the other isomer. Preferential binding of one isomer to plasma proteins may cause differences in circulating free drug and hence alter concentrations at active sites. Interactions of both isomers may differ at the active sites through which pharmacological action is mediated. Actions and levels of activity of the stereoisomers in vivo may also differ. All the pharmacological activity may reside in a single enantiomer, whereas several possibilities exist for the other enantiomer-- it may be inactive, have a qualitatively different effect, an antagonistic effect or produce greater toxicity. Two isomers may have nearly identical qualitative pharmacological activity, qualitatively similar pharmacological activity but quantitatively different potency, or qualitatively different pharmacological activity. To avoid adverse effects and optimise the therapeutic value of enantiomeric drugs, it is necessary that methods for the resolution of racemates be evolved and devolved to determine isomeric purity, establish the effectiveness of isomers of the drug, and detect the presence of an enantiomer with lower therapeutic activity and undesirable adverse effects. Even if a drug is given as a pure enantiomer, methods to discriminate between enantiomers are required because racemisation can occur both in vitro and in vivo. Methods developed for resolution of drug enantiomers should facilitate routine testing of single isomers and their metabolites, studies of pharmacological, toxicological and clinical effectiveness, routine analysis of racemates, pure enantiomers or intermediates in manufacturing processes, and investigation of the potential for inversion of an enantiopure drug substance during the early stages of drug development and therapeutic drug monitoring.     

Dosing of antidepressants--the unknown art

Data from a therapeutic drug monitoring service, in total 2,393 observations in 1,606 patients, were used to analyze factors associated with the prescribed daily doses of the tricyclic antidepressants amitriptyline and nortriptyline. The achieved concentrations in plasma were evaluated in relation to suggested therapeutic ranges. The doses of both drugs were greatly reduced with increasing age, despite the fact that age is of minor importance for their kinetics. Interactions with concomitantly given drugs were not handled by dose adjustments of the antidepressant. Therapeutic drug monitoring increased the proportion of concentrations within the therapeutic range for patients on amitriptyline, but not for those on nor-triptyline. The large interindividual kinetic variability for most antidepressants requires individualized dosing, but this individualization is performed on incorrect grounds.     

Dose-related adverse effects of anticonvulsants

The serum concentration at which a given drug has full efficacy in delivering seizure control bears no predictable relationship to the concentration at which adverse effects will appear. In theory, the threshold for adverse effects should be considerably higher than that for efficacy. For each agent this obviously happens most of the time, or the anticonvulsant would not be on the market, but there are also patients in whom this relationship is reversed. The adverse effects of this class of drugs are discussed from three points of view: the adverse effect type, the kinetic factors that so frequently determine the presence of adverse effects, and the specific characteristics of each drug. Some less well recognized adverse effects syndromes that are not strictly dose related are considered. The importance of adverse effects in therapeutic monitoring is then addressed, and some strategies for maximising efficacy without the burden of long term functional impairment or distress are discussed. The usefulness of monotherapy is stressed with due attention to rational choice of second drugs, when necessary, based on mechanisms of antiepileptic action and adverse effects profiles. While most of these symptoms evolve gradually, there are times when acute, drastic, and even life threatening clinical overdose situations present themselves. Special attention is given to these scenarios, drawing on the drug profiles and clinical pharmacokinetics that define these events to propose methods of coping with the problems efficiently and effectively.     

Capillary electrophoresis for therapeutic drug monitoring of antiepileptics

We examined the use of capillary electrophoresis for therapeutic drug monitoring of antiepileptic drugs. Micellar electrokinetic capillary chromatography (MEKC) with a diode array detector simultaneously determined concentrations of zonisamide, a new type of antiepileptic drug, and phenobarbital, phenytoin and carbamazepine, typical antiepileptic drugs, in human serum. Zonisamide levels in human serum obtained by MEKC correlated well with levels obtained by high-performance liquid chromatography. The serum levels of phenobarbital, phenytoin and carbamazepine determined by MEKC were almost equal to those obtained by fluorescence polarization immunoassay. The reproducibility of separation and quantification with MEKC for intra- and inter-day assays were appropriate. This MEKC method could provide a simple and efficient therapeutic drug monitoring method for antiepileptic drugs, especially in patients treated with a combination of zonisamide and other antiepileptic drugs. MEKC may be an attractive method for therapeutic drug monitoring, because of its specificity of separation, automation of procedure, ease of method development, low cost, small aqueous buffer amounts, speed of analysis, small injection volume and high environment-directed performance.     

Relationship of whole-blood FK506 concentrations to rejection and toxicity in liver and kidney transplants

FK506 (tacrolimus) has been shown to be a safe and effective immunosuppressant for the prevention of organ rejection after liver and kidney transplantation. Like cyclosporine, the use of FK506 has been associated with some adverse effects such as toxicity and organ rejection. Therapeutic monitoring of the whole-blood FK506 drug concentrations has been used in an effort to determine how the concentration of FK506 in the blood is related to the development of toxicity or the risk for organ rejection. Cox regression analysis of two recent clinical trials of FK506 in patients receiving kidney and liver transplants shows a significant correlation between the whole-blood FK506 concentrations and the incidence of both toxicity and organ rejection. Because of these relationships and the pharmacokinetics of FK506, therapeutic monitoring of the whole-blood FK506 levels is expected to be helpful for minimizing the risks of both toxicity and rejection in liver and kidney transplants.     

Drug-related hospitalization at a tertiary teaching center in Lebanon: incidence, associations, and relation to self-medicating behavior

OBJECTIVE: In Lebanon there is very limited restriction on drug use. Accordingly, self-medication is highly prevalent. This study examined the influence of these factors on the development of drug-related illnesses that lead to hospitalization. METHODS: Patients admitted to the medical and pediatric wards of a tertiary teaching center in Beirut, Lebanon, over a period of 6 months were interviewed and their charts were reviewed. Admissions attributable to adverse drug reactions or therapeutic failures were identified and characterized with respect to demographic factors, medical history, drug intake, and self-medicating behavior. The influence of these variables on the development of drug-related illnesses was examined by logistic regression. RESULTS: Of 1745 adults and 457 children, there were 177 (10.2%) and 36 (7.9%) drug-related illnesses, respectively. Adverse drug reactions accounted for 7.0% and 5.7% and therapeutic failures for 3.2% and 2.2% of adult and pediatric admissions, respectively. Self-medication was commonly practiced (52.6% of adults and 41.6% of children). Logistic regression analysis revealed that female sex increased the risk of adverse drug reaction in adults, whereas self-medication decreased the risk. In children, the risk of adverse drug reaction was increased in lower socioeconomic groups, whereas the risk of therapeutic failure was increased by a positive history of atopy or drug reaction. CONCLUSIONS: These results provide the first detailed analysis of the problem of drug-related illnesses in a developing country and identify a number of related or risk factors. Despite the lack of regulation of drug dispensing and the unchecked access to drugs in Lebanon, the incidence of drug-related illnesses is not different from that in Western nations. This finding may have relevance to policies of drug regulation in other countries.     

Measurement of tacrolimus (FK506) and its metabolites: a review of assay development and application in therapeutic drug monitoring and pharmacokinetic studies

Tacrolimus (FK506, Prograf) is a macrolide immunosuppressant used for the prevention of organ rejection after transplantation. Tacrolimus demonstrates considerable interindividual variation in its pharmacokinetic profile. This has caused difficulty in defining the optimum regimen and has highlighted the need for therapeutic drug monitoring. Several assay methods for the measurements of tacrolimus in biological specimens have been developed. These assay methods were used for therapeutic drug monitoring and/or pharmacokinetic studies. Two commercially available immunoassays, based on the same monoclonal antibody to tacrolimus, have been used for therapeutic drug monitoring of tacrolimus in whole blood. For pharmacokinetic studies, the assay methods were used to measure tacrolimus and its metabolites in very low concentrations in selected biological matrixes to determine the metabolic and pharmacokinetic profiles of this drug.     

Therapeutic control of plasma concentrations and long-term effect of nortriptyline in recurrent affective disorders

Based on the evidence that therapeutic plasma concentration range in fact exists for the tricyclic antidepressant drug, Nortriptyline (range 50-150 ng/ml), three different investigations were under taken in order to clarify some clinical pharmacological problems during long-term treatment with this drug. The possible prophlactic effect of the drug in recurrent affective disorders was specially examined in a group of patients with a high risk of episodes in their unipolar manic-depressive disease. The results highly demonstrate the value of monitoring plasma levels in achieving therapeutic control. Depressive relapses during treatment, for months and years, were only related to therapeutic insufficient plasma levels of the drug.     

Adaptive control of drug dosage regimens using maximum a posteriori probability Bayesian fitting

Optimal drug therapy can only be achieved if a drug is given in the right dosage regimen. Therefore the dosage regimen needs to be optimized, using the available information of the drug, the patient, and his disease. The optimization of drug therapy comprises two major steps: First, the clinician should define explicit therapeutic goals for each patient individually. Second, a strategy to achieve these goals with the greatest possible precision should be chosen. An overview of the optimization of drug therapy is presented, with special reference to maximum a posteriori probability (MAP) Bayesian fitting. Drug dosage optimization requires 1. measurement of a performance index related to the therapeutic goal, generally one or more plasma concentration measurements, 2. population pharmacokinetic parameters, including mean values, standard deviations, covariances and information on the statistical distribution, and 3. reliable software for adaptive control strategy and optimal dosage regimen calculation. The benefit of optimal drug therapy by adaptive control using MAP Bayesian fitting has been proven, resulting in improved patient outcome by improved efficacy of therapy and a reduction of adverse reactions, and in reduced costs, mainly due to a reduction of hospitalization. Newer strategies might replace the MAP Bayesian fitting procedure, if their advantage has been demonstrated convincingly, and if reliable and user-friendly software is available.     

Use of aminoglycosides in elderly patients. Pharmacokinetic and clinical considerations

Aminoglycosides still represent a mainstay in the treatment of serious infections caused by Gram-negative bacilli in elderly patients. The aging process is accompanied by various physiological changes (e.g. alterations in body composition, impairments in certain organ functions), which may affect drug disposition and, subsequently, drug action. For aminoglycosides that are eliminated by the renal route, kidney function is the key parameter that should be taken into account when dosage regimens are calculated. Because there is a progressive decline in renal function with aging, the glomerular filtration rate should be estimated for each patient. Any change in creatinine clearance (CLCR) should result in a proportional correction of the dosage regimen. Such individualised dosage of aminoglycosides is particularly important because of their narrow therapeutic indices. There are no conclusive data which indicate that age per se affects the elimination of aminoglycoside antibiotics. Overdosage may result from overestimation of renal function if crude serum creatinine (SCr) levels are used as a guide. Nomograms for the relationship between SCr and CLCR have been developed. However, nomograms should be used with caution because substantial interindividual variability in the plasma concentration-clearance relationship is still observed. Therefore, the choice of a maintenance dose based on an assessment of renal function, which change rapidly, should always be considered as preliminary, and verification by serum concentration measurements is necessary. As a result, the use of aminoglycoside serum concentration monitoring during therapy as the most important guide for dosage adjustment is particularly important in the elderly, and is indispensable in conjunction with frequent assessment of renal function. Although a matter of debate, the value of serum concentration monitoring has been demonstrated. With traditional multiple daily dosage, monitoring peak and trough concentrations has been recommended. For once daily dosage, however, no guidelines relating to therapeutic and/or toxic concentrations are available yet. In the meantime, we recommend monitoring at least trough concentrations. Once daily administration of aminoglycosides has emerged as a new mode of treatment. Compared with multiple daily administration, once daily dosage may have a number of advantages, and many clinical trials comparing the efficacy or safety of both modes have shown either superiority or equivalence of the new mode in most indications. At present, however, no data from studies of once daily administration in young compared with elderly adults are available.     

Binding of anti-double stranded (ds) DNA-positive sera to denatured (d) DNA and synthetic poly[dA-dT] x poly[dA-dT] double stranded copolymer in an ELISA format

Full dose heparin therapy is monitored by a variety of laboratory methods, of which the activated partial thromboplastin time (APTT) is the most popular. A large number of APTT reagents are currently available, with different sensitivities to heparin evident in many. Within the literature it is apparent that there is a lack of consensus, and indeed some confusion, regarding the therapeutic ranges for the APTT for standard heparin therapy in the treatment of venous thromboembolic disease. Accordingly we conducted an Australasian survey to evaluate current laboratory and clinical practices in monitoring heparin therapy, to determine the extent of variation in the approach and to stimulate the process of standardisation of acceptable procedures and methodology. Results of the survey demonstrate that currently there is no uniform practice used to establish therapeutic ranges for monitoring standard heparin therapy. Furthermore, results suggest that current practice may lead to subtherapeutic anticoagulation in many laboratories.     

The use of audit to improve clinical effectiveness in an infrequent obstetric therapy: magnesium sulphate in severe pre-eclampsia

Magnesium sulphate has been established as the drug of choice in the management of eclampsia and even when used in cases of severe pre-eclampsia it is given infrequently. It is recognised to have potentially severe toxic effects but there is a need to achieve therapeutic levels quickly enough to prevent seizures. This paper reports an audit following the introduction of a protocol for the use of magnesium sulphate in eclampsia and severe pre-eclampsia at Ninewells hospital, Dundee. Problems were identified with both the time taken to reach therapeutic levels and clinical monitoring of magnesium levels despite the use of loading doses commonly recommended. Reaudit after changes to the protocol and the introduction of an administration/monitoring chart showed a significant improvement in both monitoring and the adequacy of prophylaxis. This demonstrates how audit of clinical practice has been used to improve clinical effectiveness in an area in which a potentially toxic drug is used infrequently but with potentially life saving benefits.     

Therapeutic drug monitoring in special populations

Therapeutic drug monitoring (TDM) is commonly used to maintain "therapeutic" drug concentrations. Even in compliant patients, with "average" drug kinetics, TDM is useful to identify the causes of unwanted or unexpected responses, prevent unnecessary diagnostic testing, improve clinical outcomes, and even save lives. TDM has greatest promise in certain special populations who are: (a) prone to under- or overrespond to usual dosing regimens, (b) least able to tolerate, recognize, or communicate drug effects, or who are (c) intentionally or accidentally misdosed. TDM is especially useful in patients at the extremes of age, in adolescents, and in patients who are either taking multiple drugs or expressing unusual pharmacokinetics as a result of physiological, environmental, or genetic causes. Less-well-appreciated uses of TDM include prevention of dangerous underdosing of patients, investigation of adverse drug reactions, and identification of serious medication errors, even for a number of drugs that are not traditionally monitored. TDM can be useful for some drugs in any patient and for most drugs in some special populations.     

Perioperative monitoring of potentially toxic drugs

A list of drugs considered to have a narrow therapeutic margin are discussed. These potentially toxic drugs will be reviewed, including recommended therapeutic ranges, when therapeutic levels should be obtained, and additional laboratory studies that may be required for patients on these medications who are preparing to undergo surgery.     

Lithium neurotoxicity at low therapeutic doses Hypotheses for causes and mechanism of action following a retrospective analysis of published case reports

Lithium has been the pharmacologic treatment for the management of manic-depressive illness for many years. While the therapeutic efficacy of lithium is invaluable, it can cause a variety of neurotoxicities at normal therapeutic doses or concentrations. A systematic search through the Medline database was performed. 41 Cases of neurotoxic adverse effects of lithium at low therapeutic concentrations were observed (< 65 years, 14 males & 21 females/> 65 years, 6 females). Although a higher percentage of female subjects experienced lithium neurotoxicity, no statistically significant difference between the two groups was noted (Fisher's exact test, P = 0.07). The analysis of the data shows that among case reports of lithium neurotoxicity, drug interaction effect is an important factor. More than 50% (51.2%) of the patients received at least one neuroleptic medication with their lithium treatment, 22% received concomitantly an antidepressant, 22% an antiepileptic (carbamazepine) and 17% an anxiolytic. It is our hypothesis that these drug associations are an important contributing factor to lithium neurotoxicity. The high percentage of neurotoxicity which is associated with neuroleptics warrant caution in the daily clinical practice when these two classes of medications are combined. It is hypothesised that neuroleptics, in particular the phenothiazines, might increase lithium influx in red blood cells and that the enhanced levels of lithium in the tissue may possibly be responsible for the neurotoxic effects. Concomitant administration of medications such as neuroleptics with lithium require caution with regular clinical observations and drug plasma concentration monitoring.     

Drug administration in patients with renal insufficiency. Minimising renal and extrarenal toxicity

Renal insufficiency has been associated with an increased risk of adverse effects with many classes of medications. The risk of some, but not all, adverse effects has been linked to the patient's degree of residual renal function. This may be the result of inappropriate individualisation of those agents that are primarily eliminated by the kidney, or an alteration in the pharmacodynamic response as a result of renal insufficiency. The pathophysiological mechanism responsible for alterations in drug disposition, especially metabolism and renal excretion, is the accumulation of uraemic toxins that may modulate cytochrome P450 enzyme activity and decrease glomerular filtration as well as tubular secretion. The general principles to enhance the safety of drug therapy in patients with renal insufficiency include knowledge of the potential toxicities and interactions of the therapeutic agent, consideration of possible alternatives therapies and individualisation of drug therapy based on patient level of renal function. Although optimisation of the desired therapeutic outcomes are of paramount importance, additional pharmacotherapeutic issues for patients with reduced renal function are the prevention or minimisation of future acute or chronic nephrotoxic insults, as well as the severity and occurrence of adverse effects on other organ systems. Risk factors for the development of nephrotoxicity for selected high-risk therapies (e.g. aminoglycosides, nonsteroidal anti-inflammatory drugs, ACE inhibitors and radiographic contrast media) are quite similar and include pre-existing renal insufficiency, concomitant administration of other nephrotoxins, volume depletion and concomitant hepatic disease or congestive heart failure. Investigations of prophylactic approaches to enhance the safety of these agents in patients with renal insufficiency have yielded inconsistent outcomes. Hydration with saline prior to drug exposure has given the most consistent benefit, while sodium loading and use of pharmacological interventions [e.g. furosemide (frusemide) dopomine/dobutamine, calcium antagonists and mannitol] have resulted in limited success. The mechanisms responsible for altered dynamic responses of some agents (benzodiazepines, theophylline, digoxin and loop diuretics) in renally compromised patients include enhanced receptor sensitivity secondary to the accumulation of endogenous uraemic toxins and competition for secretion to the renal tubular site of action. Application of the pharmacotherapeutic principles discussed into clinical practice will hopefully enhance the safety of these agents and optimise patient outcomes.     

Practical treatment guide for dose individualisation in cancer chemotherapy

Dosages of anticancer drugs are usually calculated on the basis of a uniform standard, the body surface area (BSA). Although many physiological functions are proportionate to BSA, overall drug clearance is only partially related to this parameter. Consequently, following administration of equivalent drug dosages based on BSA, a wide variability in plasma drug concentrations can be found between patients, as a result of which some patients experience little toxicity while others may show severe toxic symptoms. A clear pharmacokinetic/pharmacodynamic correlation has been demonstrated for some anticancer drugs, and this relationship provides a background against which rational dose optimisation can be implemented for individual patients. The 3 strategies that can be employed for optimising dosage regimens, none based on BSA, are described and criticised. A priori adaptive dosage determination is based on the relative contribution of identifiable characteristics of patient, drug therapy and disease state that influence plasma drug concentrations; the dosage regimen is based on each patient's profile with regard to these characteristics. Although this approach is most successful with drugs whose clearance is closely tied to renal function, patient characteristics such age, obesity, serum albumin or hepatic function may be useful. The anticancer drug most closely identified with this approach is carboplatin, although dosage reduction strategies for etoposide, taxanes, anthracyclines, topotecan, oxazaphosphorines, vinca alkaloids or melphalan are advocated for patients with renal or hepatic dysfunction. The importance of pharmacogenetics for fluorouracil and mercaptopurine is also briefly discussed. The second approach consists of adaptive dosage adjustments during repetitive or continuous administration of a drug. It has been used for several years to administer methotrexate therapy and, more recently, it has been developed more fully and applied to continuous infusion of fluorouracil or etoposide. It was based, after determination of a target plasma concentration or area under the plasma drug concentration-time curve (AUC), on modification of the drug dosage during the cycle of chemotherapy or for the next cycle. Finally, the third approach of adaptive dosage adjustment with feedback control, based on population pharmacokinetics, with limited sampling strategy, may allow a feedback revision of the dosage following measurement of plasma drug concentration and comparison with the population previously studied. This approach is a theoretical strategy which has not, until now, been used prospectively in clinical oncology. For drugs such as anticancer agents with a very narrow therapeutic index, every effort should be made to minimise interpatient variability in drug exposure in order to maximise the benefit while keeping the risk of serious adverse effects at an acceptable level. This is particularly important when treatment is being given with curative intent.     

Nifedipine gastrointestinal therapeutic system versus nifedipine coat-core: comparison of efficacy via 24-hour ambulatory blood pressure monitoring

OBJECTIVE: To assess the comparable efficacy and adverse effect profile of two extended-release preparations of nifedipine--gastrointestinal therapeutic system (GITS) and coat-core (CC)--in patients with mild-to-moderate hypertension. DESIGN: Single institution, single-blind, prospective study. SETTING: Dwight David Eisenhower Army Medical Center, Fort Gordon, GA. PATIENTS: Ninety-one patients who were taking nifedipine GITS as a sole antihypertensive agent were randomized to receive either GITS or CC. After 3 weeks, 24-hour ambulatory blood pressure monitoring was conducted and an adverse effect questionnaire was administered. The patients were then crossed over to the other treatment arm and monitoring was repeated after 3 weeks. MEASUREMENTS: Mean blood pressure, heart rates, and the percentage of readings exceeding 140 mm Hg systolic and 90 mm Hg diastolic were compared for the 24-hour period. Additionally, mean blood pressures at 4-hour intervals after drug administration and heart rate during the first 8 hours of the dosage interval were compared. RESULTS: Ninety-one patients enrolled, 79 completed the study, and 62 patients were included in the efficacy analysis. A statistically significant difference (p = 0.020) was shown only in the last 4-hour systolic blood pressure. However, this difference was small (122 +/- 15 mm Hg with GITS vs. 126 +/- 14 mm Hg with CC). There was no difference in the percentage of readings exceeding 140 mm Hg systolic or 90 mm Hg diastolic. Neither dosage nor treatment order had an effect on the results. Adverse effects were reported with a greater frequency during CC therapy (40 with CC vs. 22 with GITS; p = 0.006), but were generally transient. Discontinuation of the drug was necessary in 3 patients during the CC cycle. CONCLUSIONS: GITS and CC demonstrated clinically equivalent antihypertensive efficacy in the study population. The CC produce may have a higher rate of adverse effects, but drug discontinuation was uncommon.     

Anesthesiology

During the past three decades anaesthesia-related mortality has been reduced to an extent which is more or less exclusively governed by human error. This improvement has been achieved by nearly equal progresses in drug development as well as in the development of technical devices, especially in monitoring. Nearly 80% of all anaesthetics which are used today in an anaesthetic university department were developed in the last 30 years. The search and research for better controllable compounds has caused the necessity to develop also devices which are able to deliver these substances continuously. One might therefore reason that the term pharmaceutical which today is entirely based on the term compound has in the future to be based on a combination of compound and device. The pharmacist of today and yesterday may in the future become a high-tech microsystems engineer. From an academic point of view it is unsatisfactory that the degree of therapeutic success can only be achieved and documented very incompletely. Partially this is due to the fact that the anaesthesiologists are not able to formulate their therapeutic goals, stating which higher integrative brain functions have to be reduced to what degree to guarantee an optimum therapeutic level.     

A drug experience registry

The Drug Exerience Registry is a system for the recording and filing of drug-related patient events in a readily retrievable form. The purpose of the registry is to accumulate information on adverse drug reactions, unusual therapeutic successes of failures, and other experiences that may be useful for education, research or promotion of rational drug therapy. Data are recorded on case report forms which are categorized by organ-disease system affected, the clinical event and involved drug(s). These are then filed in the clinical event file along with literature synopses that serve as guides in evaluating the incidents and determining proper therapy. A drug file serves as a cross index to the clinical event file and allows one to quickly locate clinical events involving a drug. Both files contain sufficient hospital data to allow later retrieval of additional information if needed.