Current Drug Metabolism - Volume 12, Issue 7, 2011

The increasing proportion of elderly people in all industrialized countries, along with improvement in medical technologies, has expanded the number of people affected by multiple chronic diseases and taking multiple drugs. As an example, about half of Medicare beneficiaries receive 5 or more medications [6]. Optimizing the treatment in the presence of many comorbid conditions is a challenging issue, and even more in the elderly because all of the factors on which the therapeutic decisions are usually based (e.g. scientific evidences, indications coming from guidelines, expected benefits, expected risks) may be of limited usefulness in this population. Indeed, elderly patients with comorbid conditions are frequently excluded from clinical trials [13]. As a result, clinical practice guidelines, that are based on the evidence coming from randomized trials and meta-analyses, can not be easily generalized to older people [11] without producing a substantial increase in the risk of drug-drug or drug-disease interactions [2]. Additionally, randomized clinical trials are usually not powered to detect safetyrelated outcomes [14], and therefore only data coming from observational studies are usually available. The incidence of adverse drug reactions (ADRs) in a community-dwelling elderly population is 50.1/1000 person-years, with significant impact on health and quality of life [5]. Overall comorbidity, the use of multiple medications for the treatment of different coexisting chronic diseases, female gender, and selected comorbid conditions (e.g. renal failure) are main determinants of high ADRs risk in older patients [3, 7-10, 15, 16]. However, agerelated changes in pharmacokinetics and pharmacodynamics could also be implicated [1, 4, 12]. The aim of this special issue was to provide to the reader a detailed picture of this truly challenging issue, in an attempt to integrate the views of pharmacologists and clinicians. In the first paper, Shi and Klotz summarized the most recent evidence about age-related pharmacokinetic changes. A reduced bioavailability of some drugs when active transport mechanisms are involved, an increased bioavailability of some drugs undergoing extensive first-pass metabolism, an increased volume of distribution of lipophilic drugs due to age-related changes in body composition, a reduced hepatic and renal clearance, as well as the genetic influence on metabolism are all extensively described. However, it must be recognized that the interindividual variability in drug disposition is particularly prominent in the elderly probably due to several other confounding factors (e.g. frailty, comorbidity, polypharmacy, and drug interactions). According to the paper by Trifiro and Spina, age-related changes in pharmacodynamics tend to increase the sensitivity to selected drugs, such as CNS and cardiovascular drugs, in older people. However, reduced effectiveness of conventional doses of other drugs, such as β- blockers and diuretics, was observed in elderly patients, thus supporting the idea that general rules may not be systematically applied to the effect of age-related pharmacodynamic changes. Although studies on the effect of age on drug response are generally plagued by several methodological limitations, it is worth noting that differences in drug response observed between elderly and young individuals may partly be ascribed to a decline in baseline levels of functioning with age, which means that also pharmacodynamics, and not only pharmacokinetics, may be significantly affected by frailty and comorbidity. An example of how the importance of translating the knowledge on age-related changes in pharmacokinetics and pharmacodynamics into clinical practice is provided in the paper by De Leon. The author focuses attention on anticholinergic (or antimuscarinic) drugs. These drugs are often plagued by several central (sleep disturbances, memory deficits, cognitive deficits etc.) and peripheral (decreased sweating, blurred vision, increased heart rate, and, typically, dry mouth, constipation and urinary retention) ADRs. The paper offers and explain an exhaustive list of methods to establish the muscarinic activity of a drug, presents weakness and strength of each one, and describes factors influencing muscarinic receptor response and pharmacokinetics. The knowledge about this issue is a valuable tool for clinicians when visiting patients with absolute contraindications to antimuscarinic drugs (e.g. cognitive impairment)........

Ageing is characterized by a progressive decline in the functional reserve of multiple organs and systems, which can influence drug disposition. In addition, comorbidity and polypharmacy are highly prevalent in the elderly. As ageing is associated with some reduction in first-pass metabolism, bioavailability of a few drugs can be increased. With ageing body fat increases and total body water as well as lean body mass decrease. Consequently, hydrophilic drugs have a smaller apparent volume of distribution (V) and lipophilic drugs have an increased V with a prolonged half-life. Drugs with a high hepatic extraction ratio display some age-related decrease in systemic clearance (CL), but for most drugs with a low hepatic extraction ratio, CL is not reduced with advancing age. In general, activities of cytochrome P450 enzymes are preserved in normal ageing and the genetic influence is much more striking than age effects. Drug transporters play an important role in pharmacokinetic processes, but their function and pharmacology have not yet been fully examined for agerelated effects. One third of elderly persons show no decrease in renal function (GFR>70 mL/min/1.73 m2). In about two thirds of elderly subjects, the age-related decline of renal function was associated with coexisting cardiovascular diseases and other risk factors. In the elderly a large interindividual variability in drug disposition is particularly prominent. In conclusion, the complexity of interactions between comorbidity, polypharmacy, and age-related changes in pharmacokinetics (and pharmacodynamics) justify the old and well-known dosing aphorism " start low, go slow" for aged individuals.

Aging is characterized by progressive impairment of functional capacities of all system organs, reduction in homeostatic mechanisms, and altered response to receptor stimulation. These age-related physiologic changes influence both pharmacokinetics and pharmacodynamics of drugs in elderly patients. Pharmacokinetic and pharmacodynamics changes as well as polypharmacy and comorbidities may alter significantly the effect of pharmacological treatment with advancing age. With the same drug concentration at the site of action, significant differences in the response to several drugs have been observed in older patients as compared to younger patients. Elderly patients are particularly suceptibles to the effects of frequently prescribed drugs acting on central nervous system, such as benzodiazepines, antidepressants, antipsychotics and lithium, with high potential for adverse drug reactions. Moreover, in older patients increased sensitivity to warfarin resulting in increased risk of bleeding has been previously documented. On the other hand, reduced effectiveness of conventional doses of cardiovascular drugs, such as diuretics and β-blockers, has been observed. Due to pharmacodynamic changes, therefore, dose adjustment of the above mentioned cardiovascular and psychotropic drugs is recommended in elderly. Clinicians should be aware of the age-related physiologic changes affecting several organ systems and their implications on the effect of drugs that are commonly prescribed to elderly patients.

The genetics of drug metabolizing enzymes, drug transporters and drug receptors is a very active area of multidisciplinary research, overlapping the interest of medicine, biology, pharmacology and genetics. Indeed, these proteins are virtually responsible for the metabolism, disposition and efficacy of most of available drugs. Variations in the gene encoding these proteins may account for the interindividual differences observed in drug efficacy, including severe clinical consequences such as therapeutic failures and adverse drug reactions. It is well known that the prevalence of both therapeutic failures and adverse drug reactions strongly increased in older subjects, and this did not seem to be always related to the presence of multiple pharmacological treatments, a common status in subjects aged 65 years and over. The present article explored some basic concepts of human genetics that may have important implications in the pharmacogenetics of drug metabolizing enzymes, drug transporters and receptors. We also focus the current knowledge on the genetic basis of the efficacy and the adverse drug reactions of the most common drugs used in the geriatric patient. Thus we explore the status of what we know and what we need to know to forward the application of pharmacogenetics in clinical practice, in order to introduce a personalized treatment project for the older people.

Many naturalistic studies agree that adverse drug reactions (ADRs), particularly cognitive deficits, frequently occur when medications with anticholinergic activity are used in geriatric patients. However, the studies disagree on which anticholinergic drugs may have clinical relevance. The three most important methods to establish clinically relevant anticholinergic activity are: 1) the drug's affinity for muscarinic receptors, demonstrated by in vitro studies and a profile compatible with antagonist properties; 2) serum anticholinergic activity measured by radioreceptor assay; and 3) the presence of typical antimuscarinic ADRs, such as dry mouth and constipation, in patient studies or clinical trials. More recently, brain imaging of muscarinic receptors and scales for quantifying antimuscarinic activity were developed. A comprehensive approach can be crafted only by paying attention to the pharmacodynamic and pharmacokinetic mechanisms of these drugs. ADR studies on drugs with anticholinergic activity should not only consider central muscarinic receptor blockade, but also peripheral receptor blockade. The ability to cross the blood-brain barrier is important in the drug's ADR profile. Patient personal characteristics, drug-drug interactions (DDIs) and probably genetic variations may contribute to increased ADR risk through pharmacokinetic and/or pharmacodynamic mechanisms. Sophisticated clinical designs and the evidence-based medicine approach cannot succeed unless the list of drugs of anticholinergic activity is agreed upon, and the studies include a sophisticated pharmacological approach guided by our current understanding of their pharmacodynamic and pharmacokinetic mechanisms. If one agrees that antimuscarinic ADRs are probably dose-related, future studies must consider all drugs, administration routes, doses, muscarinic receptor affinity, DDIs, and brain access.

Changes in pharmacokinetics and pharmacodynamics, associated with increasing age, are often considered the only culprits of increasing Adverse Drug Reactions (ADR) rate observed in older adults, but other factors may be responsible for a reduction in drug efficacy and increase the risk of iatrogenic illness in this population. The aging process is characterized by a high level of complexity, which makes the care of older adults and the use of medications a challenging task. In particular, comorbidity, geriatric syndromes, cognitive and functional deficits, limited life expectancy are typical conditions observed in older adults which may reduce the efficacy of prescribed drugs and increase the risk of iatrogenic illness. As a consequence, a comprehensive assessment and management of the health care problems, with the goal of recognizing and preventing potential drug-related problems and improve quality of prescribing is necessary to reduce the risk of ADR. Several studies have assessed the effect of a comprehensive geriatric assessment and management on drug prescribing and drug related illness, showing a substantial improvement in quality of prescription and a reduction in rate of ADR. In addition, clinical guidelines providing recommendations regarding the use of drugs in chronic disease rarely assess the level of complexity observed in older adults and therefore they should be applied with caution in this population.

Adverse drug reactions (ADRs) are a public health problem in older subjects, being responsible for a significant morbidity, disability and mortality. Older subjects are more susceptible to develop ADRs mainly due to polypharmacy, multimorbidity and inappropriate prescribing. The prevention of these drug related negative events represents an important aim for physicians treating older patients. Several strategies could potentially be employed, including state of the art education of medical students and physicians concerning principles of geriatric medicine and appropriate prescription in older subjects, reduction of inappropriate drug use by means of computerized decision support systems, pharmacist involvement and comprehensive geriatric assessment, and finally the identification of at risk older patients. However, there is currently a lack of scientific evidence demonstrating that these strategies can achieve a reduction in ADRs and therefore future intervention studies should be performed to evaluate the best intervention to decrease the burden of drug related problems in the older population.

Despite the growing of pharmacological options for the treatment of diabetes, epidemiological studies suggest that a substantial proportion of patients does not achieve glycemic goals and so suffers from the risk of chronic complications. This review explores the inhibition of renal glucose reabsorption as a novel approach to treat hyperglycemia. Sodium-glucose cotransporter 2 (SGLT2), a low-affinity high-capacity transporter located in the brush-border membrane of the early segment (S1) of the proximal renal tubule, accounts for about 90% of the reabsorption of glucose from tubular fluid. Competitive inhibitors of SGLT2 that are responsible for renal excretion of glucose provide a unique mechanism to potentially lower the elevated blood glucose levels in patients with diabetes. They act independently of insulin secretion, thereby minimizing the risk of hypoglycemia and weight gain, to control energy balance in a negative direction, a distinctive advantage of this class of drugs over existing oral hypoglycemic agents. Although this group of medications is still under investigation, it appears to be safe and generally well tolerated and it would be expected to improve the treatment of type 2 diabetes as monotherapy or in combination with other oral or parenteral agents. Dapagliflozin is the first agent within this class, which induces clinically meaningful reductions in FPG, PPG, HbA1c, and body weight in type 2 diabetes.

L-Carnitine is an endogenous molecule involved in fatty acid metabolism, biosynthesized within the human body using amino acids: L-lysine and L-methionine, as substrates. L-Carnitine can also be found in many foods, but red meats, such as beef and lamb, are the best choices for adding carnitine into the diet. Good carnitine sources also include fish, poultry and milk. Essentially, L-carnitine transports the chains of fatty acids into the mitochondrial matrix, thus allowing the cells to break down fat and get energy from the stored fat reserves. Recent studies have started to shed light on the beneficial effects of L-carnitine when used in various clinical therapies. Because L-carnitine and its esters help reduce oxidative stress, they have been proposed as a treatment for many conditions, i.e. heart failure, angina and weight loss. For other conditions, such as fatigue or improving exercise performance, L-carnitine appears safe but does not seem to have a significant effect. The presented review of the literature suggests that continued studies are required before L-carnitine administration could be recommended as a routine procedure in the noted disorders. Further research is warranted in order to evaluate the biochemical, pharmacological, and physiological determinants of the response to carnitine supplementation, as well as to determine the potential benefits of carnitine supplements in selected categories of individuals who do not have fatty acid oxidation defects.

Amyotrophic lateral sclerosis (ALS) is a debilitating neuro-degenerative disorder characterized by progressive loss of motor neurons. The etiology and molecular pathogenesis of cell death in most sub-types of the disease are largely unknown. The best documented cause of moto-neuron degeneration is the mutation in the superoxide dismutase-1 (SOD1) gene, which occurs in 10% of the familial forms of ALS. Discovery of RNA interference (RNAi), which plays an important role in the regulation of gene expression, has proven to be a powerful tool to study the pathogenesis and to develop innovative treatment options for hereditary diseases, including familial variants of ALS. This review summarizes current research advances in RNAi in relation to ALS.

The original map of mammalian cytochrome P450 (CYP450) residues involved in substrate recognition was prepared for the CYP2 family by Gotoh in 1992 by manual alignment of mammalian CYP450 residues with substrate recognition site (SRS) residues manually delimited from a bacterial cytochrome P450-substrate complex. Using modern structural bioinformatics tools, we have identified CYP450-ligand interactions in mammalian complexes to create a “X-ray structures” SRS map. In a parallel approach, we have built a “docking” SRS map by successful docking of 868 known substrates of 10 mammalian CYP450 isoforms and analysis of contacts made in docking solutions. We subsequently combined these maps to create a unified description of SRSs. The new map largely agrees with the original map by Gotoh with the six original SRS regions appearing in similar locations along the CYP450 sequence as in Gotoh's map. However, important differences also occur: Two new SRS regions appear before SRS1 and we have assigned them as SRS1'a and SRS1'b; SRS1 is much bigger in our map than in Gotoh's (49 aligned positions versus 28); & SRS2 and SRS3 are co-joined in our map to give a single large SRS region (60 aligned positions) we have designated as SRS(2,3), in contrast to the 9 and 10 aligned positions individually covered by SRS2 and SRS3 respectively in Gotoh's original map. These differences result in the SRS zone covering 33 % of the mammalian CYP450 sequence in our map as opposed to 16 % in Gotoh's map.