Carmelo Lafuente-Lafuente

Amiodarone concentrations in plasma and fat tissue during chronic treatment and related toxicity

AIMS To determine if amiodarone, highly lipophilic, accumulates in excess with respect to dose in fat tissue during long-term administration, and study if plasma and fat tissue concentrations are correlated with adverse effects. METHODS Trough concentrations of amiodarone and N-desethyl-amiodarone were measured simultaneously in plasma and fat tissue, in 30 consecutive patients treated with amiodarone for 3 months to 12 years. Subcutaneous adipose tissue was obtained by needle aspiration from lumbar and abdominal areas. Concentrations were measured by liquid chromatography-tandem mass spectrometry. RESULTS Plasma levels of amiodarone and N-desethyl-amiodarone were significantly correlated with daily maintenance doses (R= 0.52, P= 0.003). Amiodarone concentrations in fat tissue were four to 226 times (mean 55) higher than in plasma, and well correlated with plasma levels (R= 0.68, P < 0.001). Concentrations of amiodarone and N-desethyl-amiodarone in adipose tissue did not significantly increase with higher total cumulated doses or longer treatment duration. Nine of 12 patients who had received amiodarone for > or =2 years developed clinically important adverse effects, predominantly hypothyroidism (n= 6), compared with two of 18 patients treated for less time (relative risk 6.75; 95% confidence interval 1.8, 26). The incidence of those adverse effects was not significantly associated with amiodarone concentrations, whether in plasma or in adipose tissue. CONCLUSIONS We found no evidence of excessive or unexpected accumulation of amiodarone in fat tissue on long-term administration. Late amiodarone adverse effects, particularly hypothyroidism, are associated with longer exposure times, but do not seem to be explained by higher concentrations in plasma or in fat tissue.

Management of atrial fibrillation

#### Summary points Atrial fibrillation is the commonest sustained arrhythmia encountered in clinical practice. Its prevalence increases with age, rising from 0.7% in people aged 55-59 years to 18% in those older than 85 years.1 Consequently, the public health burden associated with atrial fibrillation is increasing.w1 The therapeutics of atrial fibrillation is evolving. In recent years, publication of several randomised controlled trials and meta-analyses have improved our understanding of the advantages and inconveniences of rate and rhythm control strategies, and effective, new non-pharmacological treatments have been introduced. New antiarrhythmic and anticoagulant drugs are expected in the near future. Atrial fibrillation is characterised by a chaotic electrical activity in the atria that induces an irregular and usually rapid contraction of the ventricles (figure 1⇓). Patients may be asymptomatic; may have mild symptoms, …

Anticoagulation du sujet âgé : nouveautés thérapeutiques

Vitamin-K antagonists (VKA) are the current standard for oral anticoagulation. However, they carry several problems in older patients: frequent bleeding complications, complex management, risk of interactions with multiple drugs. Two new classes of oral anticoagulants (NOA) are now available: direct thrombin inhibitors (dabigatran); and direct factor Xa inhibitors (rivaroxaban, apixaban) and others. Their management is easier: quickly effective after administration, they are given at fixed doses and do not need regular laboratory monitoring. Several randomized trials have shown that NOA are non-inferior to heparins and VKA for treating venous thromboembolic disease (prophylactic or curative treatment) and atrial fibrillation (prevention of associated embolisms). NOA are also being studied for long-term treatment after acute coronary syndromes. Data regarding older people is still sparse. No trial has specifically studied older patients. In the context of atrial fibrillation, subgroup analysis show similar results between patients above and below 75 years old, except for dabigatran which seems to carry more bleeding complications in people older than 75 years, specially with the highest dose employed. All NOA are eliminated at least partly by kidneys. Their dose must be reduced in moderate renal failure (filtration glomerular rate (FGR) 30 to 50 ml/min) and they are contra-indicated in severe renal failure (FGR<30 ml/min). Doses of dabigatran and apixaban should be reduced in older people too. NOA also have other unresolved problems: drug interactions are still possible, specific coagulation test to assess them must be developed, and no specific antidote is currently available in case of hemorrhagic complication.

Pharmacologie clinique et vieillissement

Clinicians must be aware that aging can lead to changes in the pharmacokinetics and pharmacodynamics of many drugs. Drug distribution may be modified with aging secondarily to the decrease of serum albumin and to modifications of body composition (increase in the proportion of fat mass and decrease of lean mass). Hepatic metabolism of several drugs is reduced with age, especially drugs which depend of hepatic blood flow or P450 cytochroms. The incidence of renal failure increase largely with age. Glomerular filtration rate should be systematically estimated in older patients and, when needed, the doses of those drugs having significant renal elimination should be adjusted. In older patients, changes in the response to drugs can also develop, concerning specially the central nervous system (increased sensibility to any neurological effect of drugs), the cardiovascular system and the renal management of water and electrolytes. In many cases, the pharmacological changes associated to age are mild and requires no dose adjustment. However, many drugs should be adapted depending on the individual situation of each patient, particularly his renal function and nutritional state. Finally, some drugs should be avoided in older patients because of a bad effectiveness/tolerance ratio compared to alternatives.

Mise au pointPharmacologie clinique et vieillissementClinical pharmacology and aging

Clinicians must be aware that aging can lead to changes in the pharmacokinetics and pharmacodynamics of many drugs. Drug distribution may be modified with aging secondarily to the decrease of serum albumin and to modifications of body composition (increase in the proportion of fat mass and decrease of lean mass). Hepatic metabolism of several drugs is reduced with age, especially drugs which depend of hepatic blood flow or P450 cytochroms. The incidence of renal failure increase largely with age. Glomerular filtration rate should be systematically estimated in older patients and, when needed, the doses of those drugs having significant renal elimination should be adjusted. In older patients, changes in the response to drugs can also develop, concerning specially the central nervous system (increased sensibility to any neurological effect of drugs), the cardiovascular system and the renal management of water and electrolytes. In many cases, the pharmacological changes associated to age are mild and requires no dose adjustment. However, many drugs should be adapted depending on the individual situation of each patient, particularly his renal function and nutritional state. Finally, some drugs should be avoided in older patients because of a bad effectiveness/tolerance ratio compared to alternatives.

Agitation iatrogène chez le sujet âgé : prévalence, causes et prise en charge☆☆☆

Key points Iatrogenic agitation is frequently drug-induced in the elderly . The management of the iatrogenic agitation is based on: a detailed analysis of the patients medications, stopping non-essential drugs, prescribing drugs to the lowest and effective dose possible. This management of the iatrogenic agitation is also based on: adjustment of drugs according to renal function and limitation of polypharmacy . Special attention is necessary when prescribing treatments for patients with cognitive impairment .

[Iatrogenic agitation in elderly patient: prevalence, aetiologies and management].

Iatrogenic agitation is frequently drug-induced in the elderly. The management of the iatrogenic agitation is based on: a detailed analysis of the patients medications, stopping non-essential drugs, prescribing drugs to the lowest and effective dose possible. This management of the iatrogenic agitation is also based on: adjustment of drugs according to renal function and limitation of polypharmacy. Special attention is necessary when prescribing treatments for patients with cognitive impairment.

Long term treatment of atrial fibrillation in elderly patients: a decision analysis.

BACKGROUND Atrial fibrillation (AF) is more frequent with age but it is not clear whether, and how, older age should influence therapeutic choice. METHODS We developed a Markov decision analytic model simulating the long term effectiveness of 4 therapeutic strategies (rate control (RateC) or rhythm control (RhythmC) using amiodarone, each combined with aspirin or warfarin) in two hypothetical cohorts of patients with persistent AF, 60 and 80 years old at baseline. Two different base risks of stroke, low and moderate/high, were analysed. Outcomes studied were: predicted mortality, quality-adjusted years (QALYs), stroke, and disability. Time horizon was 10 years. RESULTS All results applied similarly to patients 60 and 80 years old at baseline. RateC + warfarin obtained in all cases the lowest predicted mortality (0.5% to 3.9% absolute reduction). RateC + warfarin also gained the more cumulated QALYs in patients at moderate/high risk of stroke, but RateC + aspirin obtained better results in QALYs in patients at low risk of stroke. Differences between strategies in terms of QALYs were limited (0.07 to 0.25 QALY of difference). Sensitivity analysis identified four variables, the same in younger and in older patients, that could change which strategy was optimal: impact on quality of life provoked by AF and by warfarin treatment, baseline risk of stroke and risk of major bleeding on warfarin. CONCLUSIONS No important difference in the decision making between patients 60 and 80 years old was found. Several individual variables influenced the optimal choice of long term treatment of AF, but not age by itself.

Predisposing and precipitating factors for delirium in community-dwelling older adults admitted to hospital with this condition: A prospective case series

Background Factors associated with delirium among community-dwelling older adults have been poorly studied. Our aim was to describe the prevalence of predisposing and precipitating factors for delirium among patients admitted for delirium and to assess whether these factors were appropriately recognized at the first patient assessment at hospital. Methods Consecutive community-dwelling individuals admitted to three geriatric acute care units with a confirmed initial diagnosis of delirium were prospectively included. An independent investigator recorded, using a predefined form, any acute medical condition considered by the attending geriatrician to be a precipitating factor, at the first patient assessment and at the end of his stay in acute care. Results A total of 208 patients were included, 80.0% had a pre-existing cognitive or neurological disorder, or both. The most frequent precipitating factor found were infections (49.0% of all patients, mainly lung and urinary tract infections), followed by drugs (30.8%), dehydration (26.4%) and electrolytic disturbances (18.7%, mostly hyponatremia). 91% of patients had a cerebral imagery, but acute neurological conditions were found in only 18.3%. Fewer precipitating factors were found at first than at final assessment (1.4 (95%CI 1.3–1.6) versus 1.9 (95%CI 1.8–2.0) respectively, p<0.001). This difference was significant for all main categories of precipitating factors. Conclusions Infections, followed by drugs and hydro-electrolytic disorders seem to be the most frequent precipitating factors for delirium in community-dwelling elderly individuals. Early diagnostic and management of precipitating factors in these patients should be improved, as a significant number of them are missed at the initial assessment.

Zoster and postherpetic neuralgia: vaccine prevention is available

Herpes zoster (HZ) infection is a common condition in the elderly. Immunosuppression involving cellular immunity favors its occurrence. The pain is the most frequent complications of HZ. It occurs in about 30% of people aged over 70 years. The virological diagnosis of typical HZ is not useful, and the diagnosis is mainly based on clinical data. Skin care is essential to limit cutaneous damage. Antiviral drugs will reduce the risk of post-herpetic neuralgia, if they are early prescribed within 72 hours after the rash onset. Analgesia is essential and should be conducted in relation evolution. Vaccination is the most effective way to prevent the occurrence of HZ complications in the elderly, in particular post-herpetic neuralgia.