The prevalence of obesity has dramatically increased in recent years and now includes a significant proportion of the world's children, adolescents and adults. Obesity is linked to a number of co-morbidities, the most prominent being type 2 diabetes mellitus. While many agents are available to treat these conditions, the current knowledge regarding their disposition in the obese remains limited. Over the years, both direct and indirect methodologies have been utilized to assess body composition. Commonly used direct measures include underwater weighing, skinfold measurement, bioelectrical impedance analysis and dual-energy x-ray absorptiometry. Unfortunately, these methods are not readily available to the majority of clinicians. As a result, a number of indirect measures to assess body composition have been developed. Indirect measures rely on patient attributes such as height, bodyweight and sex. These size metrics are often utilized clinically and include body mass index (BMI), body surface area (BSA), ideal bodyweight (IBW), percent IBW, adjusted bodyweight, lean bodyweight (LBW) and predicted normal weight (PNWT). An understanding of how the volume of distribution (V(d)) of a drug changes in the obese is critical, as this parameter determines loading-dose selection. The V(d) of a drug is dependent upon its physiochemical properties, the degree of plasma protein binding and tissue blood flow. Obesity does not appear to have an impact on drug binding to albumin; however, data regarding alpha(1)-acid glycoprotein binding have been contradictory. A reduction in tissue blood flow and alterations in cardiac structure and function have been noted in obese individuals. At the present time, a universal size descriptor to describe the V(d) of all drugs in obese and lean individuals does not exist. Drug clearance (CL) is the primary determinant to consider when designing a maintenance dose regimen. CL is largely controlled by hepatic and renal physiology. In the obese, increases in cytochrome P450 2E1 activity and phase II conjugation activity have been observed. The effects of obesity on renal tubular secretion, tubular reabsorption, and glomerular filtration have not been fully elucidated. As with the V(d), a single, well validated size metric to characterize drug CL in the obese does not currently exist. Therefore, clinicians should apply a weight-normalized maintenance dose, using a size descriptor that corrects for differences in absolute CL between obese and non-obese individuals. The elimination half-life (t((1/2))) of a drug depends on both the V(d) and CL. Since the V(d) and CL are biologically independent entities, changes in the t((1/2)) of a drug in obese individuals can reflect changes in the V(d), the CL, or both. This review also examines recent publications that investigated the disposition of several classes of drugs in the obese--antibacterials, anticoagulants, antidiabetics, anticancer agents and neuromuscular blockers. In conclusion, pharmacokinetic data in obese patients do not exist for the majorit...

Recent studies have generated a great deal of interest in a possible role for red blood cells in the transport of nitric oxide (NO) to the microcirculation and the vascular effect of this nitric oxide in facilitating the flow of blood through the microcirculation. Many questions have, however, been raised regarding such a mechanism. We have instead identified a completely new mechanism to explain the role of red cells in the delivery of NO to the microcirculation. This new mechanism results in the production of NO in the microcirculation where it is needed. Nitrite produced when NO reacts with oxygen in arterial blood is reutilized in the arterioles when the partial pressure of oxygen decreases and the deoxygenated hemoglobin formed reduces the nitrite regenerating NO. Nitrite reduction by hemoglobin results in a major fraction of the NO generated retained in the intermediate state where NO is bound to Hb(III) and in equilibrium with the nitrosonium cation bound to Hb(II). This pool of NO, unlike Hb(II)NO, is weakly bound and can be released from the heme. The instability of Hb(III)NO in oxygen and its displacement when flushed with argon requires that reliable determinations of red blood cell NO must be performed on freshly lysed samples without permitting the sample to be oxygenated. In fresh blood samples Hb(III)NO accounts for 75% of the red cell NO with appreciably higher values in venous blood than arterial blood. These findings confirm that nitrite reduction at reduced oxygen pressures is a major source for red cell NO. The formation and potential release from the red cell of this NO could have a major impact in regulating the flow of blood through the microcirculation.Nitric oxide (NO) 1 synthesized by endothelial nitric-oxide synthase diffuses both to the smooth muscle cells as well as the lumen (1, 2). The reaction of NO with smooth muscle cell guanylate cyclase plays a crucial role in the regulation of vascular tone and blood flow (3). In the lumen NO is either oxidized by oxygen resulting in the formation of nitrite (4) or is taken up by red blood cells (5). In red blood cells, NO rapidly reacts with oxyhemoglobin to form methemoglobin (Hb(III)) and nitrate and with deoxyhemoglobin (deoxyHb) to form heme-nitrosylated hemoglobin (Hb(II)NO) (6, 7). Earlier studies, therefore, assumed that the only effect of red blood cells on the bioactivity of nitric oxide was to scavenge and inactivate NO limiting its availability for vasodilation. This perspective was challenged by studies of Stamler and co-workers (8 -13) who proposed an active role for red blood cells in the delivery of NO. Their model is based on the potential binding of NO released from arterial endothelial cells to the few vacant deoxyhemes to form Hb(II)NO and to the ␤-93 cysteine to form S-nitrosohemoglobin (SNOHb) (11). The relative affinity for these two hemoglobin sites was assumed to depend on the hemoglobin quaternary conformation with heme-bound NO favored by the T-state present in deoxygenated hemoglobin transferred to the cysteine in ...

Evidence about the association between treatment with high-risk medicines and frailty in older individuals is limited. We investigated the relationship between high-risk prescribing and frailty at baseline, as well as 2-year incident frailty, in 1,662 men ≥70 years of age. High-risk prescribing was defined as polypharmacy (≥5 medicines), hyperpolypharmacy (≥10 medicines), and by the Drug Burden Index (DBI), a dose-normalized measure of anticholinergic and sedative medicines. At baseline, frail participants had adjusted odds ratios (ORs) of 2.55 (95% confidence interval, CI: 1.69-3.84) for polypharmacy, 5.80 (95% CI: 2.90-11.61) for hyperpolypharmacy, and 2.33 (95% CI: 1.58-3.45) for DBI exposure, as compared with robust participants. Of the 1,242 men who were robust at baseline, 6.2% developed frailty over two years. Adjusted ORs of incident frailty were 2.45 (95% CI: 1.42-4.23) for polypharmacy, 2.50 (95% CI: 0.76-8.26) for hyperpolypharmacy, and 2.14 (95% CI: 1.25-3.64) for DBI exposure. High-risk prescribing may contribute to frailty in community-dwelling older men.

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Background The Drug Burden Index (DBI), a measure of exposure to anticholinergic and sedative medications, has been independently associated with physical and cognitive function in a cross-sectional analysis of community dwelling older persons participating in the Health, Aging and Body Composition (Health ABC) study. Here we evaluate the association between DBI and functional outcomes in Health ABC participants over five years. Methods DBI was calculated at years 1 (baseline), 3 and 5 and a measure of the area under the curve for DBI (AUCDB) over the whole study period was devised and calculated. Physical performance was measured using the short physical performance battery (SPPB), usual gait speed, and grip strength. The association of DBI at each time point and AUCDB with year 6 function was analyzed in data from participants with longitudinal functional measures, controlling for socio-demographics, co-morbidities and baseline function. Results Higher DBI at years 1, 3 and 5 was consistently associated with poorer function at year 6. On multivariate analysis, a one unit increase in AUCDB predicted decreases in SPPB score of 0.08 (p = 0.01), gait speed of 0.01 m/s (p=0.004), and grip strength of 0.27 kg (p=0.004) at year 6. Conclusion Increasing exposure to medication with anticholinergic and sedative effects, measured with DBI, is associated with lower objective physical function over five years in community dwelling older people.

Methylphenidate is prescribed for over 90% of children in the US diagnosed as having attention-deficit hyperactivity disorder (ADHD). Although ADHD has been widely studied, the use of methylphenidate in ADHD still poses a number of unresolved questions, including its pharmacodynamic characteristics (drug concentration-effect relationship) and the effect of long term treatment on the patient's psychopathology later in life. The objective of this review is to provide an analysis of the pharmacokinetic-pharmacodynamic properties and therapeutic effectiveness of methylphenidate that may help to answer some of these questions. Methylphenidate has 2 chiral centres, but the drug used in therapy comprises only the threo pair of enantiomers. d-threo-Methylphenidate is more potent than the l-enantiomer. Methylphenidate is administered as a racemic mixture that undergoes stereoselective clearance. Methylphenidate is a short-acting stimulant with a duration of action of 1 to 4 hours and a pharmacokinetic half-life of 2 to 3 hours. Maximum drug concentration after oral administration occurs at about 2 hours. Methylphenidate is absorbed well from the gastrointestinal tract and easily passes to the brain. Methylphenidate is efficacious for short term treatment for children with ADHD. Its mechanism of action is not understood, but may be associated with its influence on multiple neurotransmitters, especially the release and reuptake of dopamine in the striatum. There is marked individual variability in the dose-response relationship for methylphenidate, and therefore dosage must be titrated for optimal effect and avoidance of toxicity in each child. It is unclear whether this variability is predominantly pharmacokinetic or pharmacodynamic. If variable stereoselective metabolism occurs clinically, therapeutic drug monitoring of methylphenidate will require the application of chiral assay methods for the analysis of the active component, d-threo-methylphenidate. It is difficult to predict which children will have a favourable response to methylphenidate. Nonetheless, several studies have been published linking the severity of ADHD in children with improved clinical response to methylphenidate. The use of individual single-blind medication trials may be a practical solution to this problem. Additionally, the targeted condition warrants careful consideration, since different conditions (e.g. misbehaviour or poor academic performance) may require different regimens. Further studies of the relationship between the pharmacokinetic and pharmacodynamic properties of methylphenidate are required to allow the development of optimal dosage regimens.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Inappropriate medication use is common among the elderly. • Use of medications with anticholinergic and sedative properties is associated with functional impairments in older people. • Exposure to anticholinergic and sedative medications, measured with Drug Burden Index that includes the principles of dose–response and maximal effect, was associated with impairment in physical and cognitive function in two studies of older people in the USA. WHAT THIS STUDY ADDS • We evaluated Drug Burden Index in an Australian population of community‐dwelling older men, The Concord Health and Ageing in Men Project that enrolled a random sample of community‐dwelling men aged ≥70 years living in Sydney, Australia. • In this population, increasing Drug Burden Index was associated with objective impairments of physical performance and functional status. • The Drug Burden Index has broad applicability regardless of healthcare system, prescribing practices, gender or country. AIMS This study evaluated the associations of physical performance and functional status measures with the Drug Burden Index in older Australian men. The Drug Burden Index is a measure of total exposure to anticholinergic and sedative medications that incorporates the principles of dose–response and maximal effect. METHODS A cross‐sectional survey was performed on community‐dwelling older men enrolled in The Concord Health and Ageing in Men Project, Sydney, Australia. Outcomes included chair stands, walking speed over 6 m, 20‐cm narrow walk speed, balance, grip strength and Instrumental Activities of Daily Living score (IADLs). RESULTS The study population consisted of 1705 men (age 76.9 ± 5.5 years). Of the 1527 (90%) participants who reported taking medications, 21% were exposed to anticholinergic and 13% to sedative drugs. The average Drug Burden Index in the study population was 0.18 ± 0.35. After adjusting for confounders (sociodemographics, comorbidities, cognitive impairment, depression), Drug Burden Index was associated with slower walking speed (P < 0.05), slower narrow walk speed (P < 0.05), balance difficulty (P < 0.01), grip weakness (P < 0.01) and poorer performance on IADLs (P < 0.05). Associations with physical performance and function were stronger for the sedative than for the anticholinergic component of the Drug Burden Index. CONCLUSIONS Higher Drug Burden Index is associated with poorer physical performance and functional status in community‐dwelling older Australian men. The Drug Burden Index has broad applicability as a tool for assessing the impact of medications on functions that determine independence in older people.