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PubMed2001

Management of type 2 diabetes mellitus in the elderly: special considerations.

The principles of managing type 2 diabetes mellitus in the elderly are no different from those in younger patients, but the priorities and therapeutic strategies need to be cautiously individualised. The objectives of treatment are to improve glycaemic control in a stepwise approach that involves nonpharmacological methods including diet and exercise, and pharmacological therapy including mixtures of oral antihyperglycaemic agents alone or in combination with insulin. Although the goals of treatment may be the same for elderly and younger patients, certain aspects of type 2 diabetes in the elderly require special consideration. Treatment decisions are influenced by age and life expectancy, comorbid conditions and severity of the vascular complications. Adherence to dietary therapy, physical activity, and medication regimens may be compromised by comorbid conditions and psychosocial limitations. Drug-induced hypoglycaemia has been the main consideration and the most serious potential complication. In addition, the long term macrovascular and microvascular complications of type 2 diabetes are a source of significant morbidity and mortality. Indeed, vascular and neuropathic complications are already present at the time of diagnosis in a significant number of patients, and the impact of improved diabetes control depends on the age and life expectancy of the patient. Age-related changes in pharmacokinetics and the potential for adverse effects and drug interactions should also be considered when choosing appropriate pharmacological therapy. In general, a conservative and stepwise approach to the treatment of the elderly patient with type 2 diabetes is suggested; treatment may be initiated with monotherapy, followed by early intervention with a combination of oral agents including a sulphonylurea as a foundation insulin secretagogue in addition to a supplemental insulin sensitiser. Insulin therapy is eventually required if significant hyperglycaemia [glycosylated haemoglobin (HbA1c) >8%] persists despite oral combination therapy. Combination therapy with evening insulin and a long-acting sulphonylurea such as glimepiride is an effective strategy to improve hyperglycaemia in the elderly patient with type 2 diabetes in whom polypharmacy with oral agents is unsuccessful. In addition, such a regimen is simple to follow for the patient who may not be able to adhere to a more complicated insulin regimen. Hyperglycaemia in the elderly can be managed well with practical intervention and a straightforward treatment plan to enhance compliance. Optimal glycaemic control should be possible for every patient if treatment is individualised; however, strict glycaemic control may not be achievable in all patients or even desirable in many elderly patients.

Aged↗
PubMed2002

Clinically significant drug interactions with antidepressants in the elderly.

Pharmacological treatment of depression in old age is associated with an increased risk of adverse pharmacokinetic and pharmacodynamic drug interactions. Elderly patients may have multiple disease states and, therefore, may require a variety of other drugs. In addition to polypharmacy, other factors such as age-related physiological changes, diseases, genetic constitution and diet may alter drug response and, therefore, predispose elderly patients to adverse effects and drug interactions. Antidepressant drugs currently available differ in their potential for drug interactions. In general, older compounds, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), have a higher potential for interactions than newer compounds, such as selective serotonin reuptake inhibitors (SSRIs) and other relatively novel agents with a more specific mechanism of action. In particular, TCAs and MAOIs are associated with clinically significant pharmacodynamic interactions with many medications frequently prescribed to elderly patients. Moreover, TCAs may be susceptible to pharmacokinetic interactions when given in combination with inhibitors or inducers of the cytochrome P450 (CYP) isoenzymes involved in their metabolism. Because of a more selective mechanism of action, newer antidepressants have a low potential for pharmacodynamic drug interactions. However, the possibility of the serotonin syndrome should be taken into account when drugs affecting serotonergic transmission, such as SSRIs, venlafaxine or nefazodone, are coadministered with other serotonergic agents. Newer agents have a differential potential for pharmacokinetic interactions because of their selective effects on CYP isoenzymes. Within the group of SSRIs, fluoxetine and paroxetine are potent inhibitors of CYP2D6, while fluvoxamine predominantly affects CYP1A2 and CYP2C19 activity. Therefore, these agents should be closely monitored or avoided in elderly patients treated with substrates of these isoforms, especially those with a narrow therapeutic index. On the other hand, citalopram and sertraline have a low inhibitory activity on different drug metabolising enzymes and appear particularly suitable in an elderly population. Among other newer antidepressants, nefazodone is a potent inhibitor of CYP3A4 and its combination with substrates of this isoform should be avoided.

Aged↗
PubMed2002

Practical management of psoriasis in the elderly: epidemiology, clinical aspects, quality of life, patient education and treatment options.

Psoriasis in the elderly will constitute a significant challenge for the practising physician in this new millennium. Special considerations for the elderly include drug-induced or drug-aggravated psoriasis, especially for patients receiving polypharmacy or with recent worsening or poor response to conventional therapy. Other frequently encountered forms of psoriasis in the elderly include psoriatic arthritis and its complications, inverse psoriasis and potentially life-threatening complications such as erythrodermic or acute pustular psoriasis, where early recognition and systemic therapy is critical. Faced with an array of topical and systemic drug therapy options, it is of paramount importance that the physician remains focused on the holistic management of the patient, in order to achieve optimal compliance and benefit. This can be achieved through careful attention to quality-of-life issues, especially since many elderly patients may have other medical, social and economic comorbidities that can further negatively affect their overall quality of life. It is also essential that the severity of psoriasis be assessed on a more balanced, holistic scale that incorporates both physical and psychological parameters, such as the Salford Psoriasis Index. The patient and caregiver education should be multi-faceted, regularly conducted and practically orientated. Treatment goals should be kept simple and individualised for each patient, based on concomitant comorbidities, potential adverse effects, existing quality of life, self-care capability, drug history, caregiver situation, financial needs, feasibility for follow-up and patient's preferences. Topically applied medications, such as topical corticosteroids, salicylic acid, tar and dithranol preparations, calcipotriol and tazarotene, are the favoured first-line therapeutic options in the elderly. Narrowband ultraviolet B phototherapy is also well established as a standard therapy for psoriasis. Systemic therapy with agents such as methotrexate, acitretin and cyclosporin should be judiciously reserved for severe, extensive cases in view of their lower therapeutic index in the elderly. The ambulatory psoriasis treatment centre is an integral part of the overall cost-effective management of patients with psoriasis that can function as a 'one-stop' treatment and resource centre for the elderly patient.

Administration, Topical↗
PubMed2003

Demographics, assessment and management of pain in the elderly.

The prevalence of pain increases with each decade of life. Pain in the elderly is distinctly different from pain experienced by younger individuals. Cancer is a leading cause of pain; however, other conditions that cause pain such as facet joint arthritis (causing low back pain), polymyalgia rheumatica, Paget's disease, neuropathies, peripheral vascular disease and coronary disease most commonly occur in patients over the age of 50 years. Poorly controlled pain in the elderly leads to cognitive failure, depression and mood disturbance and reduces activities of daily living. Barriers to pain management include a sense of fatalism, denial, the desire to be 'the good patient', geographical barriers and financial limitations. Aging causes physiological changes that alter the pharmacokinetics and pharmacodynamics of analgesics, narrowing their therapeutic index and increasing the risk of toxicity and drug-drug interactions. CNS changes lead to an increased risk of delirium. Assessment among the verbal but cognitively impaired elderly is satisfactorily accomplished with the help of unidimensional and multidimensional pain scales. A comprehensive physical examination and pain history is essential, as well as a review of cognitive function and activities of daily living. The goal of pain management among the elderly is improvement in pain and optimisation of activities of daily living, not complete eradication of pain nor the lowest possible drug dosages. Most successful management strategies combine pharmacological and nonpharmacological (home remedies, massage, topical agents, heat and cold packs and informal cognitive strategies) therapies. A basic principle of the pharmacological approach in the elderly is to start analgesics at low dosages and titrate slowly. The WHO's three-step guideline to pain management should guide prescribing. Opioid choices necessitate an understanding of pharmacology to ensure safe administration in end-organ failure and avoidance of drug interactions. Adjuvant analgesics are used to reduce opioid adverse effects or improve poorly controlled pain. Adjuvant analgesics (NSAIDs, tricyclic antidepressants and antiepileptic drugs) are initiated prior to opioids for nociceptive and neuropathic pain. Preferred adjuvants for nociceptive pain are short-acting paracetamol (acetaminophen), NSAIDs, cyclo-oxygenase-2 inhibitors and corticosteroids (short-term). Preferred drugs for neuropathic pain include desipramine, nortriptyline, gabapentin and valproic acid. Drugs to avoid are pentazocine, pethidine (meperidine), dextropropoxyphene and opioids that are both an agonist and antagonist, ketorolac, indomethacin, piroxicam, mefenamic acid, amitriptyline and doxepin. The type of pain, and renal and hepatic function, alter the preferred adjuvant and opioid choices. Selection of the appropriate analgesics is also influenced by versatility, polypharmacy, severity and type of pain, drug availability, associated symptoms and cost.

Acetaminophen↗
PubMed2003

Treatment of pruritus associated with systemic disorders in the elderly: a review of the role of new therapies.

Generalised pruritus is common in the elderly. Idiopathic 'senile pruritus' is a diagnosis of exclusion, and an underlying systemic disorder should be sought. Thyroid disease, haematological malignancy, iron deficiency, cholestasis or renal impairment may be responsible for pruritus. Rarely pruritus may occur after cerebral infarction or as a paraneoplastic phenomenon. The mechanisms of pruritus are poorly understood. In systemic disorders, correction of the underlying disorder alleviates itch. However, when this cannot be achieved, a symptomatic approach is required. Response to treatment varies enormously and an empirical approach is often required. Topical applications are available to soothe the skin and bandaging techniques may improve their efficacy. A number of more targeted treatments are available for renal and cholestatic pruritus. Novel therapies such as thalidomide, opioid antagonists, ondansetron and phototherapy with ultraviolet (UV)-B radiation are now being used. Treatment of pruritus needs to be individualised, and the elderly present a particular challenge. Adequate delivery of simple emollients may be impossible because of physical impairment The elderly are more vulnerable to the adverse effects of treatments, comorbidities may alter the pharmacokinetics of drug metabolism and polypharmacy increases the likelihood of adverse drug interactions. Cognitive impairment can lead to poor compliance with treatment. The patient's general health, the severity of symptoms and the adverse effects of treatment all need to be considered. Most treatments are of benefit only to some patients; others derive only marginal improvement. Many of the newer treatments are unlicensed for pruritus and should preferably be administered under specialist supervision. We review the literature concerning the treatment of itch associated with systemic diseases, with particular emphasis on issues relevant to the elderly. Pruritus is a difficult symptom to treat. However, it is hoped that research into the mechanisms underlying the pruritus of systemic disease will allow a better understanding so that we should be able to look forward to more specific and effective therapies in the future.

Aged↗
PubMed2003

The role of opioid analgesics in rheumatoid disease in the elderly population.

Adequate pain therapy is an important aspect in the treatment of the elderly patient with rheumatoid disease. Problems with traditional NSAIDs include potentially serious gastrointestinal, cardiovascular and renal adverse effects, especially in the elderly. In addition, the selective cyclo-oxygenase-2 inhibitors have been associated with renal and cardiovascular adverse effects which may limit their use in the elderly with renal or cardiovascular disease. Opioids provide a treatment option for the management of pain in elderly patients with rheumatoid disease in whom pain control under standard management is poor; however, various therapeutic difficulties are encountered in the heterogeneous elderly population (increased risk of adverse effects, multimorbidity, and polypharmacy). Lower initial opioid dosage, prolonged dosage intervals and slower dosage titrations are advisable because of altered pharmacokinetics and pharmacodynamics. Kidney function should be tightly monitored and a timely use of laxatives is to be encouraged. Randomised clinical studies of opioids in musculoskeletal pain (e.g. osteoarthritis) have increasingly extended the scientific basis for their use. However, no randomised controlled clinical trials have examined the efficacy and the benefit/risk ratio of opioids in rheumatoid arthritis. Opioids also demonstrate an analgesic effect following local peripheral application. This opens the way to new therapeutic options in the future through the development of systemic peripherally selective opioids without CNS adverse effects.

Aged↗
PubMed2003

Long-acting injectable antipsychotics in the elderly: guidelines for effective use.

The elderly are at increased risk for psychosis because of age-related deterioration of cortical areas and neurochemical changes, comorbid physical illnesses, social isolation, sensory deficits and polypharmacy. The prevalence of psychiatric and neuropsychiatric disorders requiring treatment with an antipsychotic agent is expected to increase dramatically among people aged >64 years. Antipsychotic agents are effective in the treatment of schizophrenia, schizoaffective disorder, behavioural symptoms in patients with dementia, and mood disorders with psychosis. However, failure to adhere to a prescribed medication regimen by patients with psychosis is one of the most frustrating problems faced by mental healthcare providers, because of the high risk of relapse associated with partial compliance. For patients with psychosis who will not or cannot take oral medications on a regular daily basis or have other characteristics, such as memory, vision or auditory impairment, which contribute to partial compliance, long-acting injectable antipsychotic medication offers a solution. Older patients are especially at risk of adverse effects associated with traditional antipsychotic agents, such as motor effects, postural hypotension, excessive sedation, and anticholinergic effects because of age-related pharmacokinetic and pharmacodynamic factors, coexisting medical illnesses and concomitant medications. Therefore, drug dosage recommendations in the elderly are much more conservative than in younger patients. The appropriate starting dose of an antipsychotic in older individuals is 25% of the usual adult dose; total daily maintenance doses ranges from 25-50% of the adult dose. There are few studies regarding the use of depot antipsychotics in elderly patients. Studies that are available indicate that traditional antipsychotic agents given as depot injections are associated with positive outcomes in the elderly. Because the risks for extrapyramidal symptoms and tardive dyskinesia are reduced dramatically with atypical antipsychotics compared with traditional agents, the development of long-acting atypical antipsychotic formulations has been pursued. Of the atypical antipsychotics, risperidone is the first agent to be approved in a long-acting injectable formulation. Unpublished clinical data have revealed that patients treated with long-acting injectable risperidone (25mg, 50mg or 75mg) are more likely to show significant clinical improvement than placebo. In addition, hospitalisation rates decreased continuously and significantly during 1 year of treatment for patients who received long-acting injectable risperidone.Long-acting injectable antipsychotic medication should be considered for older patients for whom long-term treatment is indicated. The choice of which drug to use should be based on patients' history of response and personal preference, clinician's previous experience and pharmacokinetic properties.

Aged↗
PubMed2004

Management of autoimmune skin disorders in the elderly.

Senescence of the skin immunological system may explain why the elderly population has an increased susceptibility to certain autoimmune skin disorders. These disorders are characterised by the production of either antibodies that react with host tissue or immune effector T cells that are autoreactive. Bullous pemphigoid is the most common autoimmune blistering disease in the elderly. Although oral corticosteroids are the best established therapy, high-potency topical corticosteroids are very useful as initial treatment and, in the elderly, should be used instead of oral prednisolone wherever possible. Pemphigus is a chronic blistering disease of which there are two main subtypes: vulgaris and foliaceous. Paraneoplastic pemphigus is a unique clinical, histological and immunologically distinct autoimmune mucocutaneous disease which tends to be relentlessly progressive. Lichen sclerosus presents specific complications and a small but definite increased risk of squamous cell carcinoma in elderly patients. It is important to be aware of practical issues such as the difficulty in applying topical corticosteroids, the mainstay treatment of this condition. Dermatomyositis is an autoimmune systemic disorder where the skin and muscles are the most commonly affected organs. Tumour-associated disease occurs more commonly in elderly patients and has a poorer prognosis. Management of the disease includes sunscreens, topical or systemic corticosteroids, antimalarials, oral immunosuppressants or intravenous immunoglobulins. It is important to bear in mind that old age modifies the management of skin diseases because of physical and social circumstances as well as the unwanted adverse effects of medications. Polypharmacy results in an increased risk of drug interactions and, therefore, drug regimens need to be kept as simple as possible. Drug-induced autoimmune skin eruptions are common amongst the elderly and usually resolve when the offending drug is discontinued.

Adrenal Cortex Hormones↗
PubMed2004

Medication non-adherence in the elderly: how big is the problem?

Adherence to medication is one of the most intriguing and complex behaviours demonstrated by patients. Non-adherence to a therapeutic regimen may result in negative outcomes for patients and may be compounded in populations with multiple morbidities which require multiple drug therapy. Such a population is exemplified by the elderly. However, non-adherence may not be more prevalent in older patients and there is no consensus in the literature that age is a predictor of poor adherence. Indeed, older patients may deliberately choose not to adhere to medication (intentional non-adherence) to avoid adverse effects. Furthermore, many of the studies on adherence lack commonality in terms of how adherence is measured, the definition of an 'older' patient and the range of disease states which have been examined. Adherence may also be affected by access to medications which may be restricted by the use of formularies or insurance programmes. However, non-adherence may represent a greater risk in older people resulting in poor disease control which may be compounded with multiple morbidity and polypharmacy. A range of strategies have been implemented to try and improve adherence in this patient population. The use of forgiving drugs (those which have a prescribed dosage interval that is 50% or less the duration of drug action) may facilitate occasional lapses in drug-taking. Drug holidays (deliberate, supervised non-adherence for a fixed period of time) have been used in Parkinson's disease to reduce adverse effects. Once-daily scheduling of drug administration may offer a pragmatic approach to optimising drug therapy in some patients; this may be supplemented through the use of compliance aids. What is increasingly apparent, however, is that the role of the patient (irrespective of age) is critical in decision-making about medication, together with communication between patients and healthcare professionals. This has been articulated through the concept of concordance which has been described as a therapeutic alliance between the patient and healthcare professional. In addition, interventions employed to improve adherence must be multifaceted, and together with practical approaches (reducing unnecessary drugs and simplifying dosage regimens), the patient perspective must be considered. Good adherence should be seen as a means of achieving a satisfactory therapeutic result and not as an end in itself.

Aged↗
PubMed2005

The association of inappropriate drug use with hospitalisation and mortality: a population-based study of the very old.

BACKGROUND AND OBJECTIVE: Inappropriate prescribing is an important and possibly preventable risk factor for adverse drug reactions (ADRs) in the elderly, and hospital-based studies have shown that a large proportion of admissions is a result of ADRs. However, little is known about how inappropriate drug use (IDU) affects the elderly at the population level. The aim of this study was to explore possible associations of IDU with acute hospitalisation and mortality in an elderly population during 3 years of follow-up. PATIENTS AND METHODS: Data from a rural, population-based, longitudinal cohort study within the Kungsholmen Project, Sweden, were used. 785 participants, > or=75 years of age, had complete data on drug use and selected covariates collected during baseline investigation from 1995 to 1998, and were included in the study. Hospitalisation and mortality data during 3 years after inclusion were collected. IDU was assessed at baseline using consensus-based criteria applicable to available data (derived from Beers' criteria, Canadian criteria and clinical indicators of drug-related morbidity in older adults) with the addition of potentially dangerous drug duplication and additional potentially hazardous drug-drug interactions. IDU was defined as presence of at least one inappropriate drug regimen according to the study criteria. Logistic regression and proportional hazard models were used, respectively, to study the association of IDU with hospitalisation and mortality. RESULTS: Drugs were used on a regular or 'as needed' basis by 91.6% of the study population, with a mean of 4.4 drugs per person. IDU was common, with a prevalence of 18.6% and was associated with increased risk of at least one acute hospitalisation in community-living elderly, after adjustment for age, sex, education, comorbidity, dependency in activities of daily living (ADL) and smoking. The odds ratio was 2.72 (95% CI 1.64, 4.51). No association with mortality was found, after adjustment for age, sex, housing, education, comorbidity, ADL-dependency, smoking and body mass index. CONCLUSION: Polypharmacy and IDU are common among the elderly and IDU is associated with acute hospitalisation in community-living elderly. Although causality cannot be established with this study design, the results are consistent with the high prevalence of drug-related hospital admissions found in hospital-based studies. Our results indicate that it is desirable with current knowledge, to reduce IDU through information to physicians and careful prescribing.

Aged↗
PubMed2005

Cytochrome p450 polymorphisms in geriatric patients: impact on adverse drug reactions--a pilot study.

BACKGROUND AND OBJECTIVE: Up to 23% of the population, depending on their ethnic background, has genetically determined differences in the metabolism of drugs by the cytochrome P450 (CYP) enzymes CYP2C9, CYP2C19 and CYP2D6. The aim of this survey was to determine the relationship between genetical polymorphisms in these CYP enzymes and adverse drug reactions (ADRs) in geriatric patients. STUDY DESIGN: In a prospective 6-month cohort study of 243 patients in a geriatric rehabilitation ward, mean age 80.2 +/- 7.7 years, ADRs were identified by intensive monitoring by a pharmacoepidemiological team, consisting of pharmacists and physicians. 125 out of these 243 patients were genotyped cross-sectionally for polymorphisms of CYP2C9, CYP2C19 and CYP2D6 by the TaqMan-polymerase chain reaction. The main outcome measures were the prevalence of genetical polymorphisms and the patients' risk for developing an ADR as related to the genotype. RESULTS: Patients received an average of 14.2 drugs during hospitalisation which led to 251 ADRs in the whole cohort and 149 ADRs in the cross-sectional genotyping study. Genotype frequencies of CYP2C9 enzyme were 25.9% (n = 29) intermediate metabolisers (IMs) and 2.7% (n = 3) poor metabolisers (PMs). For the enzyme CYP2C19, 26.8% (n = 33) IMs and 0.8% (n = 1) PMs were detected. For the enzyme CYP2D6, 24.1% (n = 26) IMs and 3.7% (n = 4) PMs were found in the analysed patient population. In total, 61.6% (n = 77) of genotyped patients experienced mutations in at least one of the three cytochrome enzymes. The ADR rate did not differ significantly between patients with genetic mutations and wild-type genotype patients. Moreover, only eight out of 40 ADRs which were associated with drugs metabolised by CYP2C9, CYP2C19 or CYP2D6 were detected in patients with IM genotype and none in patients with PM genotype. CONCLUSION: In this investigation geriatric patients showed a high rate of ADRs. However, no association between the ADR rate and the patients' genotype could be detected, which most likely was a result of the small number of patient samples analysed. Although prophylactic genotyping would have not prevented ADRs in this pilot study, physicians nevertheless have to be aware of potential genetic mutations in patients with polypharmacy.

Aged↗
PubMed2005

Late-onset ankylosing spondylitis and related spondylarthropathies: clinical and radiological characteristics and pharmacological treatment options.

Ankylosing spondylitis is the prototype of related diseases commonly called spondylarthropathies which include reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel diseases (enteropathic arthritis) and undifferentiated spondylarthropathies. Ankylosing spondylitis and spondylarthropathies are generally observed in young patients but can be observed later in life or in persons >50 years of age. All the spondylarthropathy subgroups are represented in the elderly with some features particular to this age group. Indeed, radiological aspects of ankylosing spondylitis may be difficult to interpret because of the radiological changes induced by aging. Late-onset peripheral spondylarthropathies are characterised by severe disease, marked elevation of laboratory parameters of inflammation, oligoarthritis involving the lower limbs and oedema of the extremities. Psoriatic arthritis is more severe in the elderly and is associated with worse outcomes than in young patients. The clinical presentation of undifferentiated spondylarthropathy is as varied in the elderly as in young and middle-aged adults. Reactive arthritis and enteropathic arthritis are observed in the elderly more rarely. The effects of aging on drug metabolism and pharmacokinetics, together with the existence of co-morbidities and polypharmacy, are responsible for difficulties in the therapeutic management of late-onset ankylosing spondylitis or spondylarthropathies. Indeed, NSAIDs should be used with caution in older patients because of the high risk of serious gastrointestinal complications. Sulfasalazine and methotrexate have been used as disease-controlling drugs but did not prove very effective. Pamidronate and tumour necrosis factor (TNF)-alpha antagonists offer a therapeutic alternative but have not been specifically tested in the elderly. Pamidronate has been tested in young-onset ankylosing spondylitis and spondylarthropathies with conflicting results but can be used in older patients without risk of major adverse effects. TNFalpha antagonists have been adequately evaluated in ankylosing spondylitis and spondylarthropathies and are associated with dramatic improvement in clinical and biological parameters of disease activity. However, the safety profile of these agents in the elderly is not currently known and careful surveillance, in particular for the risk of infection such as tuberculosis, and/or exacerbation of chronic heart failure, is thus required when using these drugs in this age group.

Aged↗
PubMed2005

Pharmacokinetic considerations relating to tacrolimus dosing in the elderly.

Relaxation of the upper age limits for solid organ transplantation coupled with improvements in post-transplant survival have resulted in greater numbers of elderly patients receiving immunosuppressant drugs such as tacrolimus. Tacrolimus is a potent agent with a narrow therapeutic window and large inter- and intraindividual pharmacokinetic variability. Numerous physiological changes occur with aging that could potentially affect the pharmacokinetics of tacrolimus and, hence, patient dosage requirements. Tacrolimus is primarily metabolised by cytochrome P450 (CYP) 3A enzymes in the gut wall and liver. It is also a substrate for P-glycoprotein, which counter-transports diffused tacrolimus out of intestinal cells and back into the gut lumen. Age-associated alterations in CYP 3A and P-glycoprotein expression and/or activity, along with liver mass and body composition changes, would be expected to affect the pharmacokinetics of tacrolimus in the elderly. However, interindividual variation in these processes may mask any changes caused by aging. More investigation is needed into the impact aging has on CYP and P-glycoprotein activity and expression. No single-dose, intense blood-sampling study has specifically compared the pharmacokinetics of tacrolimus across different patient age groups. However, five population pharmacokinetic studies, one in kidney, one in bone marrow and three in liver transplant recipients, have investigated age as a co-variate. None found a significant influence for age on tacrolimus bioavailability, volume of distribution or clearance. The number of elderly patients included in each study, however, was not documented and may have been only small. It is likely that inter- and intraindividual pharmacokinetic variability associated with tacrolimus increase in elderly populations. In addition to pharmacokinetic differences, donor organ viability, multiple co-morbidity, polypharmacy and immunological changes need to be considered when using tacrolimus in the elderly. Aging is associated with decreased immunoresponsiveness, a slower body repair process and increased drug adverse effects. Elderly liver and kidney transplant recipients are more likely to develop new-onset diabetes mellitus than younger patients. Elderly transplant recipients exhibit higher mortality from infectious and cardiovascular causes than younger patients but may be less likely to develop acute rejection. Elderly kidney recipients have a higher potential for chronic allograft nephropathy, and a single rejection episode can be more devastating. There is a paucity of information on optimal tacrolimus dosage and target trough concentration in the elderly. The therapeutic window for tacrolimus concentrations may be narrower. Further integrated pharmacokinetic-pharmacodynamic studies of tacrolimus are required. It would appear reasonable, based on current knowledge, to commence tacrolimus at similar doses as those used in younger patients. Maintenance dose requirements over the longer term may be lower in the elderly, but the increased variability in kinetics and the variety of factors that impact on dosage suggest that patient care needs to be based around more frequent monitoring in this age group.

Aged↗
PubMed2005

Underutilisation of opioids in elderly patients with chronic pain: approaches to correcting the problem.

The impact of poorly managed chronic pain on the quality of life of elderly patients and the problems related to its management are widely acknowledged. Underutilisation of opioids is a major component of poor pain management in this group of patients, despite good evidence for the effectiveness of opioids and published guidelines directing their usage. Reasons for this underutilisation are, among others, poor assessment of pain in this age group; fear of polypharmacy and opiophobia; and avoidance of opioids because of concerns about tolerance, physical dependence, addiction and adverse effects. This review suggests approaches to overcome these barriers to opioid usage, such as regular pain assessments, education to overcome opiophobia, rational prescribing, utilisation of less conventional opioids and non-oral routes of administration, avoidance of inappropriate opioids, opioid rotation, and education about managing or preventing adverse effects, the reasons why opioid therapy may be unsuccessful, and the effects of psychological factors on the pain experience. This more rational and knowledge-based approach to the use of opioids in the management of chronic pain in the elderly population should correct the current problems with underprescribing in this age group.

Aged↗
PubMed2005

Outpatient medications and hip fractures in the US: a national veterans study.

BACKGROUND: Certain medications have been linked to falls. One of the most severe fall-related injuries in the elderly is a hip fracture. OBJECTIVE: The objective of this study was to examine the use of medications known to increase fall risk that were prescribed on an outpatient basis to veterans prior to hospital admission for hip fracture. METHODS: We identified and analysed the use of outpatient fall-related medications in 2212 unique patients with hip fractures admitted in fiscal year 2003 to Veterans Health Administration hospitals compared with that for matched controls (exact match for age and sex) admitted for acute myocardial infarction (MI) or pneumonia. We analysed the medications selected from the three drug categories most often linked with an increased risk for falls. These categories included medications that affected the cardiovascular (CVS), CNS or the musculoskeletal system (MSS). The unit of analysis was the hip fracture linked with outpatient medications in the study group compared with matched control groups of patients with hospitalisations for an acute MI or pneumonia. RESULTS: Of the 2212 hip-fracture patients, 70% had fall-related medications prior to hospitalisation for hip fracture. The most notable differences in usage were seen in the drug classes antiepileptics/barbiturates, antidepressants (2-fold difference in use of selective serotonin reuptake inhibitors [SSRIs] and tricyclic antidepressants [TCAs]), and antiparkinson's drugs (nearly 4-fold difference between cases and controls). There were also notable differences in usage of antipsychotics (3-fold difference for hip-fracture cases compared with acute MI) and cholinesterase inhibitors (nearly 2-fold difference for hip-fracture cases compared with pneumonia or acute MI). The most notable differences in polypharmacy combinations were CVS and CNS categories with differences of 9.44% (absolute) and 43% (relative) for hip-fracture patients over acute MI, and 4.83% (absolute) and 18% (relative) for hip-fracture patients over pneumonia patients. CONCLUSIONS: This is the first national Veterans Health Administration hip fracture hospitalisation study that temporally linked outpatient fall-related medications in hip-fracture patients with matched controls. We found that of veterans with hip-fracture hospitalisations, 70% were prescribed outpatient medications from selected major drug categories that may potentially increase fall risk. Moreover, over one-third of hip-fracture patients received concomitant prescriptions of drugs from multiple selected drug categories. Hip-fracture patients, compared with matched controls of acute MI and pneumonia, had the largest pronounced differences in prescribed medications in the antiepileptics, antidepressants, antipsychotics and antiparkinson's drug classes. Although a randomised clinical trial is the 'gold standard' for determining causation issues, exposing patients, particularly the elderly, to the potential risk of injurious falls would raise serious patient safety research approval issues. If the relationship between selected drugs and falls is indeed to some extent causative, future retrospective multivariate analyses could quantify the magnitude of these effects.

Accidental Falls↗
PubMed2006

Adverse effects of atypical antipsychotics in the elderly: a review.

Use of antipsychotic medication is very common in the elderly and often an essential therapy. However, successful treatment in the elderly requires appropriate multidimensional assessment of the patient, knowledge of possible multiple co-morbidities, and awareness of the complexities of polypharmacy, age-dependent changes in pharmacokinetics and pharmacodynamics, and drug-drug interactions in this age group. Antipsychotics are known to have a number of adverse effects. New antipsychotics, such as amisulpride, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, zotepine and aripiprazole, may interact with both dopamine and serotonin receptors. However, compared with conventional antipsychotics, they are less likely to cause extrapyramidal symptoms and are better tolerated in the elderly. At the same time, consistent differences between atypical antipsychotics have been demonstrated. Use of clozapine, for example, is limited by the risk of agranulocytosis, whereas this is not a disadvantage of olanzapine, risperidone, quetiapine and, more recently, ziprasidone, which are being widely used with good results in schizophrenia. However, use of the latter agents to treat the behavioural and psychological symptoms of dementia has been restricted because of recent observations of increased cardiovascular events in patients taking risperidone and olanzapine treatment. Nonetheless, careful review of the literature suggests that the available evidence does not support any causal relationship between use of risperidone or olanzapine and cardiovascular events. This article focuses on some of the main adverse effects commonly reported during administration of atypical antipsychotics to elderly patients. Such effects may be partly explained by age-related changes in pharmacokinetics and pharmacodynamics, and partly by the characteristics of the drugs themselves and their different receptor binding profiles.

Age Factors↗
PubMedDate not supplied

Pharmacokinetic drug interactions of commonly used anticancer drugs.

With the use of combination chemotherapy as well as a wide range of symptomatic therapies (e.g. analgesics and antiemetics) for the treatment of patients with cancer, the field of oncology practises polypharmacy to an extreme degree. The risk for a drug interaction under these conditions is high, and the pharmacological characteristics of the anti-cancer drugs, such as steep dose-response curves, low therapeutic indices and severe toxicities, suggest that even small changes in the pharmacokinetic profile of the affected drug could significantly alter its toxicity or efficacy. In this review, drug interactions which quantitatively affect the absorption, distribution, biotransformation or excretion of the commonly used anticancer drugs are described. Most of the significant drug interactions involving this class of drugs occur at the level of biotransformation and excretion. For example, the renal excretion of methotrexate by glomerular filtration and tubular secretion is affected by a number of weak organic acids, such as probenecid, salicylates and penicillin, which compete for tubular secretion, resulting in delayed clearance of methotrexate. The best described example of an interaction at the level of biotransformation is the effect of allopurinol on the catabolism of 6-mercaptopurine. By inhibiting xanthine oxidase, allopurinol blocks the first-pass metabolism of 6-mercaptopurine following its oral administration, leading to a 4- to 5-fold increase in plasma concentrations. Known drug interactions may potentially be used to enhance the antitumour activity of a drug--for instance, the administration of tetrahydrouridine (a cytidine deaminase inhibitor) with cytarabine in an attempt to block its rapid inactivation to uridine arabinoside. Overall, little information is available concerning the pharmacokinetic interactions of anticancer drugs with each other and with other classes of drugs in man, in part because the high incidence of toxicity and treatment failure, and empirical dosing methods, obscure the recognition of possible interactions. Awareness on the part of the clinician and more extensive pharmacokinetic investigation will be needed to recognise, document and avoid potentially harmful pharmacokinetic drug interactions involving this class of drugs.

Animals↗
PubMed1996

Clinically significant pharmacokinetic drug interactions with carbamazepine. An update.

Carbamazepine is one of the most commonly prescribed antiepileptic drugs and is also used in the treatment of trigeminal neuralgia and psychiatric disorders, particularly bipolar depression. Because of its widespread and long term use, carbamazepine is frequently prescribed in combination with other drugs, leading to the possibility of drug interactions. The most important interactions affecting carbamazepine pharmacokinetics are those resulting in induction or inhibition of its metabolism. Phenytoin, phenobarbital (phenobarbitone) and primidone accelerate the elimination of carbamazepine, probably by stimulating cytochrome P450 (CYP) 3A4, and reduce plasma carbamazepine concentrations to a clinically important extent. Inhibition of carbamazepine metabolism and elevation of plasma carbamazepine to potentially toxic concentrations can be caused by stiripentol, remacemide, acetazolamide, macrolide antibiotics, isoniazid, metronidazole, certain antidepressants, verapamil, diltiazem, cimetidine, danazol and (dextropropoxyphene) propoxyphene. In other cases, toxic symptoms may result from elevated plasma concentrations of the active metabolite carbamazepine-10,11-epoxide, due to the inhibition of epoxide hydrolase by valproic acid (sodium valproate), valpromide, valnoctamide and progabide. Carbamazepine is a potent inducer of CYP3A4 and other oxidative enzyme system in the liver, and it may also increase glucuronyltransferase activity. This results in the acceleration of the metabolism of concurrently prescribed anticonvulsants, particularly valproic acid, clonazepam, ethosuximide, lamotrigine, topiramate, tiagabine and remacemide. The metabolism of many other drugs such as tricyclic antidepressants, antipsychotics, steroid oral contraceptives, glucocorticoids, oral anticoagulants, cyclosporin, theophylline, chemotherapeutic agents and cardiovascular drugs can also be induced, leading to a number of clinically relevant drug interactions. Interactions with carbamazepine can usually be predicted on the basis of the pharmacological properties of the combined drug, particularly with respect to its therapeutic index, site of metabolism and ability to affect specific drug metabolising isoenzymes. Avoidance of unnecessary polypharmacy, selection of alternative agents with lower interaction potential, and careful dosage adjustments based on serum drug concentration monitoring and clinical observation represent the mainstays for the minimisation of risks associated with these interactions.

Analgesics, Non-Narcotic↗