Use of medications on the elderly | Medicina Universitaria

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A: capillary malformation (port-wine stain: diffuse, irregular borders and dim color) on the lateral face of the thorax and abdomen, lymphatic cyst on the axillary region. B: scoliosis and capillary malformation on the back of the chest and abdomen. C: increase in the volume of the fingers secondary to lymphedema. D: hypertrophy and lymphedema of the lower extremities. E: venous malformation in the medial aspect of the upper third of the left leg. F: acute complication of lymphedema: onicocriptosis and cellulitis of the first toe." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Felipe G. Rendón-Elías, Marely Hernández-Sánchez, Rosemberg Albores-Figueroa, Fernando Félix Montes-Tapia, Luis Humberto Gómez-Danés" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Felipe G." "apellidos" => "Rendón-Elías" ] 1 => array:2 [ "nombre" => "Marely" "apellidos" => "Hernández-Sánchez" ] 2 => array:2 [ "nombre" => "Rosemberg" "apellidos" => "Albores-Figueroa" ] 3 => array:2 [ "nombre" => "Fernando Félix" "apellidos" => "Montes-Tapia" ] 4 => array:2 [ "nombre" => "Luis Humberto" "apellidos" => "Gómez-Danés" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X1665579614676056?idApp=UINPBA00004N" "url" => "/16655796/0000001600000065/v0_201607061452/X1665579614676056/v0_201607061453/en/main.assets" ] "en" => array:13 [ "idiomaDefecto" => true "titulo" => "Use of medications on the elderly" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "199" "paginaFinal" => "206" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Alejandra Lorena Tamez-Peña, Héctor Eloy Tamez-Pérez, Anamaría Peña-Lazo, Jorge Ocampo-Candiani, Juan Francisco Torres-Pérez" "autores" => array:5 [ 0 => array:3 [ "nombre" => "Alejandra Lorena" "apellidos" => "Tamez-Peña" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 1 => array:3 [ "nombre" => "Héctor Eloy" "apellidos" => "Tamez-Pérez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "affb" ] ] ] 2 => array:3 [ "nombre" => "Anamaría" "apellidos" => "Peña-Lazo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "affc" ] ] ] 3 => array:3 [ "nombre" => "Jorge" "apellidos" => "Ocampo-Candiani" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 4 => array:3 [ "nombre" => "Juan Francisco" "apellidos" => "Torres-Pérez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "affd" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Dermatology Services, “Dr. José Eleuterio González” University Hospital, Monterrey, Nuevo León, México" "etiqueta" => "a" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Office of Research, School of Medicine, UANL, Monterrey, Nuevo León, México" "etiqueta" => "b" "identificador" => "affb" ] 2 => array:3 [ "entidad" => "Dermatology, Private Practice, Monterrey, Nuevo León, México" "etiqueta" => "c" "identificador" => "affc" ] 3 => array:3 [ "entidad" => "Geriatrics Services, “Dr. José Eleuterio González” University Hospital, Monterrey, Nuevo León, México " "etiqueta" => "d" "identificador" => "affd" ] ] ] ] "textoCompleto" => "Introduction According to the World Health Organization (WHO), any individual who is more than 60 years old is considered elderly or an older person. This definition applies for most industrialized countries and the UN.1 The number of elderly is increasing worldwide with over 200 million older people, and an increase of 30% is expected in the next few years.1 In Mexico, in 2010 the National Institute of Statistics and Geography (INEGI by its Spanish acronym) recorded over 11 million elderly in its census,2 and according to the projections by the National Population Council, by the year 2050 older people will represent 28% of the Mexican population, with approximately 36 million people.3 Nowadays, the elderly population is growing twice as fast as the country’s population growth rate. The increase in life expectancy has an impact in terms of health, which is reflected in a substantial increase in chronic degenerative diseases, thus making the technological and economic development that this epidemiologic transition requires necessary, with a demand for multidisciplinary medical strategies. Prescription and consumption of medications has increased among the geriatric population, hence the presence of adverse pharmacological events. The objective of this document is to make a brief review of the main physiological changes of the elderly, as well as summarizing the contribution of consensuses about prescriptions in this population.Pharmacology in the elderly The elderly population presents physiological and pharmacologic changes which make it especially susceptible to presenting secondary or adverse events to medications, even with commonly used pharmaceutics.4,5 The need to know about prescriptions, clinic pharmacology and use of medication in the geriatric population becomes evident, in addition to preparing social, economic and health systems for current and future population demographic changes.6-8 It is estimated that people over 65 consume 25-50% of all prescribed pharmaceutics, and are responsible for 70% of the total pharmaceutical expenditure.9 Different studies have calculated that two thirds of geriatric patients receive an inappropriate dosage of medication, especially those with renal elimination.10-12 Moreover, the harmful effects of the pharmaceutics may have safety consequences and economically affect the health system.13 Approximately 30% of hospital admissions of older patients is linked to the toxic effects of pharmaceutics. The related adverse effects of pharmaceutics have been associated with preventable problems, like depression, constipation, falls, immobility, confusion and hip injuries.13 In a study conducted in patients who live in retirement homes, it was proved that approximately two thirds of residents had an ADR in a period of four years and out of them 1 in 7 required hospitalization.14 In the US in 2012 problems related to medications caused 106 000 deaths with a cost of 85 billion dollars. Other authors have calculated the ADR-related expenditure to be $76.6 billion in outpatient care, $20 billion in hospitals and $4 billion in nursing homes.13,15Physical changes in the elderly Physiologically, the elderly is in a state characterized by a reduction in functional reserves and their ability to adapt,6,16-18 which suggests a different response to that of a young patient when dealing with a disease or the administration of certain medication. Proper knowledge of the changes in pharmacokinetics and pharmacodynamics in the elderly is necessary for a correct prescription, which minimizes or avoids adverse effects of medications.6,18-20 Variability in response to pharmacological intervention is conditioned by genetic factors, age, diseases, interactions and prescription compliance, which results in alterations in the pharmacokinetics and pharmacodynamics profiles, in addition to the frequent atypical presentations of diseases and the administration of multiple medications.21,22 Pharmacokinetics Pharmacokinetics determine the relationship between a medication administration and the concentration which it reaches in the body with time (in relationship with the dosage, presentation, frequency and form of administration), and despite the fact that many changes of these parameters have been described, inter-individual variability is the rule.6,18,19 Bioavailability refers to the proportion of the medication that reaches circulation, and it is a function of the form of administration, the chemical properties of the medication and the absorption and amount of dosage which is eliminated through the hepatic metabolism of the first step before reaching circulation.6,17 Bioavailability is affected by age, because absorption becomes slower, increasing the necessary time to reach maximum concentration in plasma. Some medications require an acid environment for its absorption, like ketoconazole, ampicillin or iron, and may have a decline of their bioavailability from 5 to 10%, as a result of hypochlorhydria secondary to atrophic gastritis or treatment with H2 antagonists and proton-bomb inhibitors.17-19 In the elderly, the hepatic metabolism of the first step is diminished, and oral medication bioavailability which goes through this process is greater.17,18 Distribution volume depends on the plasma’s union to protein, on water and lipid proportion and on tissue perfusion. The latter may decrease with age, causing a slower distribution, and a reduction of the dosage load with most medications should be considered.17,18 Concerning water and lipids proportion, body fat in the elderly is considered to increase between 20 and 40% and corporal water decreases by 10 to 15%, leading to an increase in concentration of water-soluble medications and a slower elimination of fat-soluble medications.18-21 Some medications which present a lower distribution volume in the elderly are digoxin, cimetidine, gentamicin, phenytoin and theophylline, among others, and this translates to high plasmatic levels of the medications.18 The most important elimination mechanisms are hepatic and renal. Hepatic metabolism in older people has a substantial decrease in its activity and there are also changes in the gastrointestinal system, like a decrease in gastric acid secretion and intestinal motility.6,19 This decrease in elimination rate prolongs medications’ half-lives and carries with it the need to increase administration intervals.6,18 This occurs with medications like acetaminophen, amitriptyline, barbiturates, ibuprofen, lidocaine, prazosin, propranolol, salicilates and warfarin, among others.18 Pharmacodynamics Pharmacodynamics describes the effects of medications in tissue (what medications cause in the body).6-18 Although it can be altered by age, these changes have not been thoroughly studied. Almost every action of the medications are mediated by a interaction of medication molecules with tissue receptors, and these can be altered by hormones, neurotransmitters and transportation systems, among others, and the central nervous and cardiovascular systems play a very important role.6 Pharmacogenetics Genetic variation is one of the causes of versatility in responses to medications and is estimated to contribute between 20 and up to 95%, even though the genetic expression can also be related to age and environmental factors.6 The aging process itself and the presentation of diseases have polygenic causes, thus the response to many medications can also be altered by polymorphisms in genes that may not be responsible for the pharmacokinetic or are not its direct target.6 In table 1 there is a summary of the main physiological changes linked to age.<img alt="Table 1 Principal physiological changes in the elderly" src="304v16n65-90367606fig1.jpg"></img>Adverse effects of the use of medications in geriatrics Prescription errors in the elderly population are generally related to pharmacological changes, inadequate orientation about dosage modification, and lack of recommendations or guides about safety of some medications in the geriatric population.21,22 Sometimes, randomized and controlled studies do not include patients over 65 years, consequently the results on the safety of some medications cannot be generalized to this population. Adverse effects of medications include adverse reactions and prescription errors. An adverse medication reaction (AMR) is defined as any undesired sign or symptom which appears after medication administration at therapeutic doses. A severe or extremely severe AMR is one which requires hospitalization or causes irreversible damage including death.1,6,18 Adverse reactions are classified based on their relation with a medication in five groups (A-E). Type A is linked to the medication’s pharmacologic action, predictable or dosage-associated (pharmacokinetic changes, medication-medication, medication-food or medication-disease interactions), and represent most of the adverse effects. In group B there is no relation with pharmacologic actions and are independent of dosage, these are less frequent but more severe (allergic reactions, cytotoxic, idiosyncratic, etc.), and are unpredictable.22,23 The reactions of group C are related to prolonged and continuous use of a medication, such as dependency reactions or tachyphylaxis. Group D refers to late or long-term reactions like teratogenicity, and carcinogesis and group E is produced when a medication is suspended (“rebound effect”). However, there are many classification systems. Mallet et al suggest a simple approach to the problem, and summarizes it in three categories, which are adverse reactions by pharmacologic interactions; patients who consume multiple medications and/or have multiple diseases (nine or more medications and five or more comorbidities); and the “prescription cascade” phenomenon, where the adverse effect of a medication leads to the prescription of another agent which at the same time causes a new secondary effect which would add a new medication.23-25 Most adverse reactions to medications in hospitalized elderly are type A and therefore represent predictable reactions and are potentially preventable.26,27 The medications that relate the most to adverse reactions and events are medications used to treat cardiovascular diseases, followed by rheumatologic and endocrinological medications, and this corresponds with the frequency and morbidity of these diseases in Mexico.27 Polypharmacy The use of concomitant medications is justified in the treatment of multiple chronic diseases. Polypharmacy is a term which describes patients who receive multiple medications, and in the elderly, this represents the rule rather than the exception.16,17 According to data from population studies in the United States, 90% of the elderly consume at least a weekly medication, over 55% of women and 44% of men of advanced age consume five medications or more, and 40% of residents in nursing homes consume over eight weekly medications.4,5,16 With this practice the risk of AMR increases drastically, because on many occasions, there are duplicates of the same kind of medication, and the adverse effects are not identified, leading to a prescription cascade.23-25,28 Adverse reactions may be difficult to detect in elderly patients because they frequently have atypical presentations, like lethargy, confusion, falls, constipation and depression. Nursing homes residents are the most vulnerable of this group.28 An appropriate use of medications in geriatrics? With the purpose of minimizing the problems that emerge as a consequence of inappropriate prescription of medications in the elderly, consensus criteria have been developed in order to improve safety among this population. Beers criteria Beers et al,28 in 1999, supported by a group of experts in geriatrics, geriatric pharmacology, psychopharmacology and pharmacoepidemiology, in addition to the revision of scientific literature, developed a consensus of medications used in the elderly and their frequent adverse effects. Criterion were developed which have been widely used to describe treatment patterns and educate and inform clinical doctors. A revision of these criteria was made in 199729 and later in 200330 to reevaluate new products, to reassess the severity assigned to each medication and to identify new situations or major considerations. The application of these criteria have allowed an improvement of pharmacological therapy safety, since it identifies risk factors associated with prescription and suggests safety improvement programs. Beers’ criteria grouped medications into two groups; medications which should be avoided by the elderly because of their inefficacy or representation of an unnecessary risk, having other alternatives (table 2), and those medications which should not be used in the elderly even when they meet specific medical requirements (table 3). Moreover it stresses the importance of identifying prescription cascade.13<img alt="Table 2 Medications specifically inappropriate for the elderly" src="304v16n65-90367606fig2.jpg"></img><img alt="Table 3 Medications specifically inappropiate for the elderly by clinical diagnosis" src="304v16n65-90367606fig3.jpg"></img> Medications mostly implicated in adverse events are cardiovascular, antibiotics, diuretics, anticoagulants, hypoglycemiants, steroids, opiates, anticholinergics, benzodiazepines and non-steroidal anti-inflammatory, among others. While Beers’ criteria is very useful, there are some limitations in their use. Some medications listed as inappropriate, may have acceptable applications; likewise, there are medications which are not included and may confer risk with their use.7,31,32 The InterRAI Corporation is a network of researchers and clinics from 30 different countries around the world, and it has developed and standardized instruments for geriatric care currently being used in many countries. These instruments provide valid scales in geriatric patients, important in clinical practice, which may have a positive effect on individual care and treatment.7,33 In 2009, Hanlon et al conducted a consensus in order to establish guidelines for the use of oral medications with renal elimination used in the elderly. The obtained results were in the form of two recommendations, medications which should be avoided in patients with a renal function of <30 mL/min like chlorpropamide, colchicine, cotrimoxazole, glyburide, meperidine, nitrofurantoin, probenecid, propoxyphene, spironolactone and triamterene; and those which require dosage reduction or a more ample administration interval, like acyclovir, amantadine, ciprofloxacin, gabapentin, memantine, ranitidine, rimantadine and valacyclovir. Frequently used medications which require renal adjustment can be found in table 4.<img alt="Table 4 Commonly used medications that require renal adjustment" src="304v16n65-90367606fig4.jpg"></img> Two identification tools to identify mistakes in prescriptions for the elderly were developed with the use of the English acronyms STOPP (screening tool of older persons’ prescription) and START (screening tool to alert to right treatment); identifying those medications which should be avoided, as well as those appropriate in the treatment of the elderly. The most commonly used medications are mentioned in tables 5 and 6.34 These studies proved that the potential omission of adequate medications in the elderly is as prevalent as the inclusion of inappropriate medications which should be avoided.5,34 A multidisciplinary team allows for a better quality in the attention of the elderly, and adequate prescriptions and an optimal control with a decrease of AMR.<img alt="Table 5 Medications inappropriate for patients over 65 years, STOPP (Screening Tool of Older Persons’ Prescription)" src="304v16n65-90367606fig5.jpg"></img><img alt="Table 6 Medications appropriate for patients over 65 years. START (Screening Tool to Alert to Right Treatment)" src="304v16n65-90367606fig6.jpg"></img>Education for prescriptions and general standards The challenge in prescribing medicine to the elderly The elderly have approximately 3 times more prescriptions than younger people. While the metabolism characteristics of geriatric patients which affect medication pharmacology are not modifiable, the choice of medication, length of the treatment and dosages are decisions which depend on the doctor, and are factors which can be optimized with the right knowledge and proper training in the treatment of geriatric patients. Every new medication must be evaluated in the following contexts: pharmacokinetic, pharmacodynamics and changes related to age regarding body composition and physiology.28 While on occasion there are differences between geriatric guidelines and clinical practices from country to country, and the prescription is strongly influenced by feedback strategies and national forms, it is important to harmonize clinical and political recommendations as well as effective measures applied to our population in order to improve medical prescription. Planning of an integral systemic approach to the elderly and teaching strategies for continuous medical education, represent an essential component of a quality medical education.35-36 Some important points to consider, with the purpose of improving the quality of prescriptions in the geriatric population, are: to conduct an integral assessment of patients, in the medical, functional, mental and social aspects; to use medications of proven efficacy, known toxicity and with experience of use in the geriatric population, to periodically review medications prescribed by different doctors, including dosage and length; to avoid unnecessary medication; periodical monitoring and evaluation of therapeutic objectives and whether or not these are properly being met; prescribe medications with fewer adverse reactions and interactions; choose medications with easily recognizable presentations and administration intervals which allow for adequate compliance; search for the minimum effective dosage and increase progressively if necessary, as well as educate the patient and personnel responsible for their care on the proper administration, which avoids self-medication.8-9, 24, 35,36 Conclusions The elderly present physiological changes which affect the pharmacology of the medications used. Pharmacological studies cannot always extrapolate a medicine’s effect on the elderly, thus the most important challenge is to achieve optimal pharmacotherapy individualization. The application of consensus criteria during prescription helps the clinic in the decision-making process and functions as a tool to minimize problems associated with the use of medications. Prescription must be based on general standards or principles of the use of medications in the elderly, whose main objective is to decrease the use of multiple medications and increase safety and treatment adhesion. Physicians who attend the elderly should integrate their individual clinical experience with the best external evidence and comprehensible information in prognosis, limitations, preferences, family support and cost of treatment. A multidisciplinary approach and assistance coordination are indispensable in order to optimize this process.<hr></hr> Received: November 2013; Accepted: July 2014 *Corresponding author: Servicio de Dermatología, Hospital Universitario “Dr. José Eleuterio González”, de la Universidad Autónoma de Nuevo León, Ave. Francisco I. Madero Pte. s/n y Ave. Gonzalitos, Col. Mitras Centro, C.P. 64460 Monterrey, Nuevo León, México. E-mail address:<a href="mailto:lorale@hotmail.com" class="elsevierStyleCrossRefs">lorale@hotmail.com</a> (A.L. Tamez Peña)." "pdfFichero" => "304v16n65a90367606pdf001.pdf" "tienePdf" => true "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec686844" "palabras" => array:3 [ 0 => "Elderly" 1 => "Adverse effect" 2 => "Medical prescription" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:1 [ "resumen" => " The elderly constitute a growing world population group, with more than 200 million people over 60 years of age. This fact has increased the detection of chronic-degenerative diseases, as well as the prescription and consumption of medicines. The elderly are particularly susceptible to adverse drug events or interactions with other drugs due to their physiological changes, genetic predisposition and environmental exposure. It becomes necessary to adapt the health systems with integral and multidisciplinary approaches suitable to this demographic change, as the knowledge about appropriate prescription, clinical pharmacology and medication use in the elderly has become essential. It has been shown that about two thirds of elderly patients receive inappropriate drug doses, and a substantial percentage of their hospital admissions are associated with potentially preventable toxic effects of drugs. To date, expert criteria, error detection tools and educational prescription plans have been developed by expert consensus for the safe use of drugs in the geriatric population. The objective of this study is a brief review of the principal physiological changes in an older adult, and summarize the contributions of the consensuses on prescription." ] ] "multimedia" => array:12 [ 0 => array:8 [ "identificador" => "tbl1" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "304v16n65-90367606fig1.jpg" "imagenAlto" => 529 "imagenAncho" => 2091 "imagenTamanyo" => 152956 ] ] ] ] ] "descripcion" => array:1 [ "en" => "Principal physiological changes in the elderly" ] ] 1 => array:8 [ "identificador" => "tbl2" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "304v16n65-90367606fig2.jpg" "imagenAlto" => 1150 "imagenAncho" => 2104 "imagenTamanyo" => 295945 ] ] ] ] ] "descripcion" => array:1 [ "en" => "Medications specifically inappropriate for the elderly" ] ] 2 => array:8 [ "identificador" => "tbl3" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "304v16n65-90367606fig3.jpg" "imagenAlto" => 708 "imagenAncho" => 2095 "imagenTamanyo" => 179308 ] ] ] ] ] "descripcion" => array:1 [ "en" => "Medications specifically inappropiate for the elderly by clinical diagnosis" ] ] 3 => array:8 [ "identificador" => "tbl4" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "304v16n65-90367606fig4.jpg" "imagenAlto" => 1354 "imagenAncho" => 2083 "imagenTamanyo" => 216954 ] ] ] ] ] "descripcion" => array:1 [ "en" => "Commonly used medications that require renal adjustment" ] ] 4 => array:8 [ "identificador" => "tbl5" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "304v16n65-90367606fig5.jpg" "imagenAlto" => 2570 "imagenAncho" => 2104 "imagenTamanyo" => 679953 ] ] ] ] ] "descripcion" => array:1 [ "en" => "Medications inappropriate for patients over 65 years, STOPP (Screening Tool of Older Persons’ Prescription)" ] ] 5 => array:8 [ "identificador" => "tbl6" "etiqueta" => "Table 6" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "304v16n65-90367606fig6.jpg" "imagenAlto" => 1125 "imagenAncho" => 2104 "imagenTamanyo" => 309277 ] ] ] ] ] "descripcion" => array:1 [ "en" => "Medications appropriate for patients over 65 years. 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Use of medications on the elderly

Alejandra Lorena Tamez-Peñaa, Héctor Eloy Tamez-Pérezb, Anamaría Peña-Lazoc, Jorge Ocampo-Candiania, Juan Francisco Torres-Pérezd

a Dermatology Services, Dr. José Eleuterio González University Hospital, Monterrey, Nuevo León, México

b Office of Research, School of Medicine, UANL, Monterrey, Nuevo León, México

c Dermatology, Private Practice, Monterrey, Nuevo León, México

d Geriatrics Services, Dr. José Eleuterio González University Hospital, Monterrey, Nuevo León, México

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    "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introduction </span></p><p class="elsevierStylePara"> According to the World Health Organization &#40;WHO&#41;&#44; any individual who is more than 60 years old is considered elderly or an older person&#46; This definition applies for most industrialized countries and the UN&#46;<span class="elsevierStyleSup">1</span> The number of elderly is increasing worldwide with over 200 million older people&#44; and an increase of 30&#37; is expected in the next few years&#46;<span class="elsevierStyleSup">1</span></p><p class="elsevierStylePara"> In Mexico&#44; in 2010 the National Institute of Statistics and Geography &#40;INEGI by its Spanish acronym&#41; recorded over 11 million elderly in its census&#44;<span class="elsevierStyleSup">2</span> and according to the projections by the National Population Council&#44; by the year 2050 older people will represent 28&#37; of the Mexican population&#44; with approximately 36 million people&#46;<span class="elsevierStyleSup">3</span> Nowadays&#44; the elderly population is growing twice as fast as the country&#8217;s population growth rate&#46;</p><p class="elsevierStylePara"> The increase in life expectancy has an impact in terms of health&#44; which is reflected in a substantial increase in chronic degenerative diseases&#44; thus making the technological and economic development that this epidemiologic transition requires necessary&#44; with a demand for multidisciplinary medical strategies&#46; Prescription and consumption of medications has increased among the geriatric population&#44; hence the presence of adverse pharmacological events&#46; The objective of this document is to make a brief review of the main physiological changes of the elderly&#44; as well as summarizing the contribution of consensuses about prescriptions in this population&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Pharmacology in the elderly </span></p><p class="elsevierStylePara"> The elderly population presents physiological and pharmacologic changes which make it especially susceptible to presenting secondary or adverse events to medications&#44; even with commonly used pharmaceutics&#46;<span class="elsevierStyleSup">4&#44;5</span> The need to know about prescriptions&#44; clinic pharmacology and use of medication in the geriatric population becomes evident&#44; in addition to preparing social&#44; economic and health systems for current and future population demographic changes&#46;<span class="elsevierStyleSup">6-8</span> It is estimated that people over 65 consume 25-50&#37; of all prescribed pharmaceutics&#44; and are responsible for 70&#37; of the total pharmaceutical expenditure&#46;<span class="elsevierStyleSup">9</span> Different studies have calculated that two thirds of geriatric patients receive an inappropriate dosage of medication&#44; especially those with renal elimination&#46;<span class="elsevierStyleSup">10-12</span> Moreover&#44; the harmful effects of the pharmaceutics may have safety consequences and economically affect the health system&#46;<span class="elsevierStyleSup">13</span></p><p class="elsevierStylePara"> Approximately 30&#37; of hospital admissions of older patients is linked to the toxic effects of pharmaceutics&#46; The related adverse effects of pharmaceutics have been associated with preventable problems&#44; like depression&#44; constipation&#44; falls&#44; immobility&#44; confusion and hip injuries&#46;<span class="elsevierStyleSup">13</span></p><p class="elsevierStylePara"> In a study conducted in patients who live in retirement homes&#44; it was proved that approximately two thirds of residents had an ADR in a period of four years and out of them 1 in 7 required hospitalization&#46;<span class="elsevierStyleSup">14</span> In the US in 2012 problems related to medications caused 106 000 deaths with a cost of 85 billion dollars&#46; Other authors have calculated the ADR-related expenditure to be &#36;76&#46;6 billion in outpatient care&#44; &#36;20 billion in hospitals and &#36;4 billion in nursing homes&#46;<span class="elsevierStyleSup">13&#44;15</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Physical changes in the elderly </span></p><p class="elsevierStylePara"> Physiologically&#44; the elderly is in a state characterized by a reduction in functional reserves and their ability to adapt&#44;<span class="elsevierStyleSup">6&#44;16-18</span> which suggests a different response to that of a young patient when dealing with a disease or the administration of certain medication&#46; Proper knowledge of the changes in pharmacokinetics and pharmacodynamics in the elderly is necessary for a correct prescription&#44; which minimizes or avoids adverse effects of medications&#46;<span class="elsevierStyleSup">6&#44;18-20</span></p><p class="elsevierStylePara"> Variability in response to pharmacological intervention is conditioned by genetic factors&#44; age&#44; diseases&#44; interactions and prescription compliance&#44; which results in alterations in the pharmacokinetics and pharmacodynamics profiles&#44; in addition to the frequent atypical presentations of diseases and the administration of multiple medications&#46;<span class="elsevierStyleSup">21&#44;22</span></p><p class="elsevierStylePara"> Pharmacokinetics</p><p class="elsevierStylePara"> Pharmacokinetics determine the relationship between a medication administration and the concentration which it reaches in the body with time &#40;in relationship with the dosage&#44; presentation&#44; frequency and form of administration&#41;&#44; and despite the fact that many changes of these parameters have been described&#44; inter-individual variability is the rule&#46;<span class="elsevierStyleSup">6&#44;18&#44;19</span></p><p class="elsevierStylePara"> Bioavailability refers to the proportion of the medication that reaches circulation&#44; and it is a function of the form of administration&#44; the chemical properties of the medication and the absorption and amount of dosage which is eliminated through the hepatic metabolism of the first step before reaching circulation&#46;<span class="elsevierStyleSup">6&#44;17</span> Bioavailability is affected by age&#44; because absorption becomes slower&#44; increasing the necessary time to reach maximum concentration in plasma&#46; Some medications require an acid environment for its absorption&#44; like ketoconazole&#44; ampicillin or iron&#44; and may have a decline of their bioavailability from 5 to 10&#37;&#44; as a result of hypochlorhydria secondary to atrophic gastritis or treatment with H<span class="elsevierStyleInf">2</span> antagonists and proton-bomb inhibitors&#46;<span class="elsevierStyleSup">17-19</span> In the elderly&#44; the hepatic metabolism of the first step is diminished&#44; and oral medication bioavailability which goes through this process is greater&#46;<span class="elsevierStyleSup">17&#44;18</span></p><p class="elsevierStylePara"> Distribution volume depends on the plasma&#8217;s union to protein&#44; on water and lipid proportion and on tissue perfusion&#46; The latter may decrease with age&#44; causing a slower distribution&#44; and a reduction of the dosage load with most medications should be considered&#46;<span class="elsevierStyleSup">17&#44;18</span> Concerning water and lipids proportion&#44; body fat in the elderly is considered to increase between 20 and 40&#37; and corporal water decreases by 10 to 15&#37;&#44; leading to an increase in concentration of water-soluble medications and a slower elimination of fat-soluble medications&#46;<span class="elsevierStyleSup">18-21</span></p><p class="elsevierStylePara"> Some medications which present a lower distribution volume in the elderly are digoxin&#44; cimetidine&#44; gentamicin&#44; phenytoin and theophylline&#44; among others&#44; and this translates to high plasmatic levels of the medications&#46;<span class="elsevierStyleSup">18</span></p><p class="elsevierStylePara"> The most important elimination mechanisms are hepatic and renal&#46; Hepatic metabolism in older people has a substantial decrease in its activity and there are also changes in the gastrointestinal system&#44; like a decrease in gastric acid secretion and intestinal motility&#46;<span class="elsevierStyleSup">6&#44;19</span> This decrease in elimination rate prolongs medications&#8217; half-lives and carries with it the need to increase administration intervals&#46;<span class="elsevierStyleSup">6&#44;18</span> This occurs with medications like acetaminophen&#44; amitriptyline&#44; barbiturates&#44; ibuprofen&#44; lidocaine&#44; prazosin&#44; propranolol&#44; salicilates and warfarin&#44; among others&#46;<span class="elsevierStyleSup">18 </span></p><p class="elsevierStylePara"> Pharmacodynamics</p><p class="elsevierStylePara"> Pharmacodynamics describes the effects of medications in tissue &#40;what medications cause in the body&#41;&#46;<span class="elsevierStyleSup">6-18</span> Although it can be altered by age&#44; these changes have not been thoroughly studied&#46; Almost every action of the medications are mediated by a interaction of medication molecules with tissue receptors&#44; and these can be altered by hormones&#44; neurotransmitters and transportation systems&#44; among others&#44; and the central nervous and cardiovascular systems play a very important role&#46;<span class="elsevierStyleSup">6 </span></p><p class="elsevierStylePara"> Pharmacogenetics</p><p class="elsevierStylePara"> Genetic variation is one of the causes of versatility in responses to medications and is estimated to contribute between 20 and up to 95&#37;&#44; even though the genetic expression can also be related to age and environmental factors&#46;<span class="elsevierStyleSup">6</span> The aging process itself and the presentation of diseases have polygenic causes&#44; thus the response to many medications can also be altered by polymorphisms in genes that may not be responsible for the pharmacokinetic or are not its direct target&#46;<span class="elsevierStyleSup">6</span> In table 1 there is a summary of the main physiological changes linked to age&#46;</p><p class="elsevierStylePara"><img alt="Table 1 Principal physiological changes in the elderly" src="304v16n65-90367606fig1.jpg"></img></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Adverse effects of the use of medications in geriatrics </span></p><p class="elsevierStylePara"> Prescription errors in the elderly population are generally related to pharmacological changes&#44; inadequate orientation about dosage modification&#44; and lack of recommendations or guides about safety of some medications in the geriatric population&#46;<span class="elsevierStyleSup">21&#44;22</span></p><p class="elsevierStylePara"> Sometimes&#44; randomized and controlled studies do not include patients over 65 years&#44; consequently the results on the safety of some medications cannot be generalized to this population&#46; Adverse effects of medications include adverse reactions and prescription errors&#46; An adverse medication reaction &#40;AMR&#41; is defined as any undesired sign or symptom which appears after medication administration at therapeutic doses&#46; A severe or extremely severe AMR is one which requires hospitalization or causes irreversible damage including death&#46;<span class="elsevierStyleSup">1&#44;6&#44;18</span> Adverse reactions are classified based on their relation with a medication in five groups &#40;A-E&#41;&#46; Type A is linked to the medication&#8217;s pharmacologic action&#44; predictable or dosage-associated &#40;pharmacokinetic changes&#44; medication-medication&#44; medication-food or medication-disease interactions&#41;&#44; and represent most of the adverse effects&#46; In group B there is no relation with pharmacologic actions and are independent of dosage&#44; these are less frequent but more severe &#40;allergic reactions&#44; cytotoxic&#44; idiosyncratic&#44; etc&#46;&#41;&#44; and are unpredictable&#46;<span class="elsevierStyleSup">22&#44;23</span> The reactions of group C are related to prolonged and continuous use of a medication&#44; such as dependency reactions or tachyphylaxis&#46; Group D refers to late or long-term reactions like teratogenicity&#44; and carcinogesis and group E is produced when a medication is suspended &#40;&#8220;rebound effect&#8221;&#41;&#46;</p><p class="elsevierStylePara"> However&#44; there are many classification systems&#46; Mallet et al suggest a simple approach to the problem&#44; and summarizes it in three categories&#44; which are adverse reactions by pharmacologic interactions&#59; patients who consume multiple medications and&#47;or have multiple diseases &#40;nine or more medications and five or more comorbidities&#41;&#59; and the &#8220;prescription cascade&#8221; phenomenon&#44; where the adverse effect of a medication leads to the prescription of another agent which at the same time causes a new secondary effect which would add a new medication&#46;<span class="elsevierStyleSup">23-25</span> Most adverse reactions to medications in hospitalized elderly are type A and therefore represent predictable reactions and are potentially preventable&#46;<span class="elsevierStyleSup">26&#44;27</span></p><p class="elsevierStylePara"> The medications that relate the most to adverse reactions and events are medications used to treat cardiovascular diseases&#44; followed by rheumatologic and endocrinological medications&#44; and this corresponds with the frequency and morbidity of these diseases in Mexico&#46;<span class="elsevierStyleSup">27 </span></p><p class="elsevierStylePara"> Polypharmacy</p><p class="elsevierStylePara"> The use of concomitant medications is justified in the treatment of multiple chronic diseases&#46; Polypharmacy is a term which describes patients who receive multiple medications&#44; and in the elderly&#44; this represents the rule rather than the exception&#46;<span class="elsevierStyleSup">16&#44;17</span></p><p class="elsevierStylePara"> According to data from population studies in the United States&#44; 90&#37; of the elderly consume at least a weekly medication&#44; over 55&#37; of women and 44&#37; of men of advanced age consume five medications or more&#44; and 40&#37; of residents in nursing homes consume over eight weekly medications&#46;<span class="elsevierStyleSup">4&#44;5&#44;16</span></p><p class="elsevierStylePara"> With this practice the risk of AMR increases drastically&#44; because on many occasions&#44; there are duplicates of the same kind of medication&#44; and the adverse effects are not identified&#44; leading to a prescription cascade&#46;<span class="elsevierStyleSup">23-25&#44;28</span></p><p class="elsevierStylePara"> Adverse reactions may be difficult to detect in elderly patients because they frequently have atypical presentations&#44; like lethargy&#44; confusion&#44; falls&#44; constipation and depression&#46;</p><p class="elsevierStylePara"> Nursing homes residents are the most vulnerable of this group&#46;<span class="elsevierStyleSup">28 </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">An appropriate use of medications in geriatrics&#63; </span></p><p class="elsevierStylePara"> With the purpose of minimizing the problems that emerge as a consequence of inappropriate prescription of medications in the elderly&#44; consensus criteria have been developed in order to improve safety among this population&#46;</p><p class="elsevierStylePara"> Beers criteria</p><p class="elsevierStylePara"> Beers et al&#44;<span class="elsevierStyleSup">28</span> in 1999&#44; supported by a group of experts in geriatrics&#44; geriatric pharmacology&#44; psychopharmacology and pharmacoepidemiology&#44; in addition to the revision of scientific literature&#44; developed a consensus of medications used in the elderly and their frequent adverse effects&#46; Criterion were developed which have been widely used to describe treatment patterns and educate and inform clinical doctors&#46; A revision of these criteria was made in 1997<span class="elsevierStyleSup">29</span> and later in 2003<span class="elsevierStyleSup">30</span> to reevaluate new products&#44; to reassess the severity assigned to each medication and to identify new situations or major considerations&#46; The application of these criteria have allowed an improvement of pharmacological therapy safety&#44; since it identifies risk factors associated with prescription and suggests safety improvement programs&#46;</p><p class="elsevierStylePara"> Beers&#8217; criteria grouped medications into two groups&#59; medications which should be avoided by the elderly because of their inefficacy or representation of an unnecessary risk&#44; having other alternatives &#40;table 2&#41;&#44; and those medications which should not be used in the elderly even when they meet specific medical requirements &#40;table 3&#41;&#46; Moreover it stresses the importance of identifying prescription cascade&#46;<span class="elsevierStyleSup">13</span></p><p class="elsevierStylePara"><img alt="Table 2 Medications specifically inappropriate for the elderly" src="304v16n65-90367606fig2.jpg"></img></p><p class="elsevierStylePara"><img alt="Table 3 Medications specifically inappropiate for the elderly by clinical diagnosis" src="304v16n65-90367606fig3.jpg"></img></p><p class="elsevierStylePara"> Medications mostly implicated in adverse events are cardiovascular&#44; antibiotics&#44; diuretics&#44; anticoagulants&#44; hypoglycemiants&#44; steroids&#44; opiates&#44; anticholinergics&#44; benzodiazepines and non-steroidal anti-inflammatory&#44; among others&#46;</p><p class="elsevierStylePara"> While Beers&#8217; criteria is very useful&#44; there are some limitations in their use&#46; Some medications listed as inappropriate&#44; may have acceptable applications&#59; likewise&#44; there are medications which are not included and may confer risk with their use&#46;<span class="elsevierStyleSup">7&#44;31&#44;32</span></p><p class="elsevierStylePara"> The InterRAI Corporation is a network of researchers and clinics from 30 different countries around the world&#44; and it has developed and standardized instruments for geriatric care currently being used in many countries&#46; These instruments provide valid scales in geriatric patients&#44; important in clinical practice&#44; which may have a positive effect on individual care and treatment&#46;<span class="elsevierStyleSup">7&#44;33</span></p><p class="elsevierStylePara"> In 2009&#44; Hanlon et al conducted a consensus in order to establish guidelines for the use of oral medications with renal elimination used in the elderly&#46; The obtained results were in the form of two recommendations&#44; medications which should be avoided in patients with a renal function of &#60;30 mL&#47;min like chlorpropamide&#44; colchicine&#44; cotrimoxazole&#44; glyburide&#44; meperidine&#44; nitrofurantoin&#44; probenecid&#44; propoxyphene&#44; spironolactone and triamterene&#59; and those which require dosage reduction or a more ample administration interval&#44; like acyclovir&#44; amantadine&#44; ciprofloxacin&#44; gabapentin&#44; memantine&#44; ranitidine&#44; rimantadine and valacyclovir&#46; Frequently used medications which require renal adjustment can be found in table 4&#46;</p><p class="elsevierStylePara"><img alt="Table 4 Commonly used medications that require renal adjustment" src="304v16n65-90367606fig4.jpg"></img></p><p class="elsevierStylePara"> Two identification tools to identify mistakes in prescriptions for the elderly were developed with the use of the English acronyms STOPP &#40;screening tool of older persons&#8217; prescription&#41; and START &#40;screening tool to alert to right treatment&#41;&#59; identifying those medications which should be avoided&#44; as well as those appropriate in the treatment of the elderly&#46; The most commonly used medications are mentioned in tables 5 and 6&#46;<span class="elsevierStyleSup">34</span> These studies proved that the potential omission of adequate medications in the elderly is as prevalent as the inclusion of inappropriate medications which should be avoided&#46;<span class="elsevierStyleSup">5&#44;34</span> A multidisciplinary team allows for a better quality in the attention of the elderly&#44; and adequate prescriptions and an optimal control with a decrease of AMR&#46;</p><p class="elsevierStylePara"><img alt="Table 5 Medications inappropriate for patients over 65 years&#44; STOPP &#40;Screening Tool of Older Persons’ Prescription&#41;" src="304v16n65-90367606fig5.jpg"></img></p><p class="elsevierStylePara"><img alt="Table 6 Medications appropriate for patients over 65 years&#46; START &#40;Screening Tool to Alert to Right Treatment&#41;" src="304v16n65-90367606fig6.jpg"></img></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Education for prescriptions and general standards</span></p><p class="elsevierStylePara"> The challenge in prescribing medicine to the elderly</p><p class="elsevierStylePara"> The elderly have approximately 3 times more prescriptions than younger people&#46; While the metabolism characteristics of geriatric patients which affect medication pharmacology are not modifiable&#44; the choice of medication&#44; length of the treatment and dosages are decisions which depend on the doctor&#44; and are factors which can be optimized with the right knowledge and proper training in the treatment of geriatric patients&#46;</p><p class="elsevierStylePara"> Every new medication must be evaluated in the following contexts&#58; pharmacokinetic&#44; pharmacodynamics and changes related to age regarding body composition and physiology&#46;<span class="elsevierStyleSup">28</span></p><p class="elsevierStylePara"> While on occasion there are differences between geriatric guidelines and clinical practices from country to country&#44; and the prescription is strongly influenced by feedback strategies and national forms&#44; it is important to harmonize clinical and political recommendations as well as effective measures applied to our population in order to improve medical prescription&#46;</p><p class="elsevierStylePara"> Planning of an integral systemic approach to the elderly and teaching strategies for continuous medical education&#44; represent an essential component of a quality medical education&#46;<span class="elsevierStyleSup">35-36</span> Some important points to consider&#44; with the purpose of improving the quality of prescriptions in the geriatric population&#44; are&#58; to conduct an integral assessment of patients&#44; in the medical&#44; functional&#44; mental and social aspects&#59; to use medications of proven efficacy&#44; known toxicity and with experience of use in the geriatric population&#44; to periodically review medications prescribed by different doctors&#44; including dosage and length&#59; to avoid unnecessary medication&#59; periodical monitoring and evaluation of therapeutic objectives and whether or not these are properly being met&#59; prescribe medications with fewer adverse reactions and interactions&#59; choose medications with easily recognizable presentations and administration intervals which allow for adequate compliance&#59; search for the minimum effective dosage and increase progressively if necessary&#44; as well as educate the patient and personnel responsible for their care on the proper administration&#44; which avoids self-medication&#46;<span class="elsevierStyleSup">8-9&#44; 24&#44; 35&#44;36 </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conclusions </span></p><p class="elsevierStylePara"> The elderly present physiological changes which affect the pharmacology of the medications used&#46; Pharmacological studies cannot always extrapolate a medicine&#8217;s effect on the elderly&#44; thus the most important challenge is to achieve optimal pharmacotherapy individualization&#46;</p><p class="elsevierStylePara"> The application of consensus criteria during prescription helps the clinic in the decision-making process and functions as a tool to minimize problems associated with the use of medications&#46; Prescription must be based on general standards or principles of the use of medications in the elderly&#44; whose main objective is to decrease the use of multiple medications and increase safety and treatment adhesion&#46;</p><p class="elsevierStylePara"> Physicians who attend the elderly should integrate their individual clinical experience with the best external evidence and comprehensible information in prognosis&#44; limitations&#44; preferences&#44; family support and cost of treatment&#46; A multidisciplinary approach and assistance coordination are indispensable in order to optimize this process&#46;</p><hr></hr><p class="elsevierStylePara"> Received&#58; November 2013&#59; <br></br> Accepted&#58; July 2014</p><p class="elsevierStylePara"> &#42;Corresponding author&#58; <br></br> Servicio de Dermatolog&#237;a&#44; <br></br> Hospital Universitario &#8220;Dr&#46; Jos&#233; Eleuterio Gonz&#225;lez&#8221;&#44; <br></br> de la Universidad Aut&#243;noma de Nuevo Le&#243;n&#44; <br></br> Ave&#46; Francisco I&#46; Madero Pte&#46; s&#47;n y Ave&#46; Gonzalitos&#44; Col&#46; Mitras Centro&#44; <br></br> C&#46;P&#46; 64460 Monterrey&#44; Nuevo Le&#243;n&#44; M&#233;xico&#46; <span class="elsevierStyleItalic"><br></br> E-mail address&#58;</span><a href="mailto&#58;lorale&#64;hotmail&#46;com" class="elsevierStyleCrossRefs">lorale&#64;hotmail&#46;com</a> &#40;A&#46;L&#46; Tamez Pe&#241;a&#41;&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara"> The elderly constitute a growing world population group&#44; with more than 200 million people over 60 years of age&#46; This fact has increased the detection of chronic-degenerative diseases&#44; as well as the prescription and consumption of medicines&#46; The elderly are particularly susceptible to adverse drug events or interactions with other drugs due to their physiological changes&#44; genetic predisposition and environmental exposure&#46; It becomes necessary to adapt the health systems with integral and multidisciplinary approaches suitable to this demographic change&#44; as the knowledge about appropriate prescription&#44; clinical pharmacology and medication use in the elderly has become essential&#46;</p> <p class="elsevierStylePara"> It has been shown that about two thirds of elderly patients receive inappropriate drug doses&#44; and a substantial percentage of their hospital admissions are associated with potentially preventable toxic effects of drugs&#46; To date&#44; expert criteria&#44; error detection tools and educational prescription plans have been developed by expert consensus for the safe use of drugs in the geriatric population&#46; The objective of this study is a brief review of the principal physiological changes in an older adult&#44; and summarize the contributions of the consensuses on prescription&#46;</p>"
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                            3 => "Frijters DH"
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Article information

ISSN: 16655796
Original language: English

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	69	12	81
2024 October	521	129	650
2024 September	479	65	544
2024 August	442	52	494
2024 July	419	62	481
2024 June	449	64	513
2024 May	641	110	751
2024 April	961	109	1070
2024 March	736	92	828
2024 February	518	40	558
2024 January	531	64	595
2023 December	606	161	767
2023 November	596	136	732
2023 October	717	180	897
2023 September	437	83	520
2023 August	299	46	345
2023 July	282	41	323
2023 June	299	79	378
2023 May	406	71	477
2023 April	312	69	381
2023 March	300	84	384
2023 February	185	42	227
2023 January	232	86	318
2022 December	298	50	348
2022 November	439	82	521
2022 October	300	53	353
2022 September	266	56	322
2022 August	154	37	191
2022 July	178	35	213
2022 June	211	31	242
2022 May	269	41	310
2022 April	297	69	366
2022 March	266	52	318
2022 February	242	66	308
2022 January	239	34	273
2021 December	179	48	227
2021 November	320	82	402
2021 October	188	27	215
2021 September	159	32	191
2021 August	165	35	200
2021 July	130	28	158
2021 June	159	30	189
2021 May	343	52	395
2021 April	789	99	888
2021 March	431	40	471
2021 February	301	44	345
2021 January	361	43	404
2020 December	249	44	293
2020 November	309	57	366
2020 October	195	34	229
2020 September	265	34	299
2020 August	217	38	255
2020 July	269	30	299
2020 June	289	59	348
2020 May	302	43	345
2020 April	308	54	362
2020 March	240	21	261
2020 February	205	23	228
2020 January	132	15	147
2019 December	99	20	119
2019 November	110	14	124
2019 October	98	13	111
2019 September	89	12	101
2019 August	88	6	94
2019 July	81	17	98
2019 June	100	27	127
2019 May	133	35	168
2019 April	73	31	104
2019 March	54	10	64
2019 February	35	18	53
2019 January	44	4	48
2018 December	14	7	21
2018 November	27	5	32
2018 October	88	5	93
2018 September	91	7	98
2018 August	31	2	33
2018 July	33	1	34
2018 June	21	2	23
2018 May	47	6	53
2018 April	43	1	44
2018 March	25	0	25
2018 February	17	0	17
2018 January	14	2	16
2017 December	9	0	9
2017 November	22	1	23
2017 October	27	0	27
2017 September	7	1	8
2017 August	14	4	18
2017 July	20	2	22
2017 June	16	8	24
2017 May	27	9	36
2017 April	15	5	20
2017 March	13	24	37
2017 February	26	1	27
2017 January	9	1	10
2016 December	17	0	17
2016 November	25	8	33
2016 October	28	1	29
2016 September	8	0	8
2016 August	15	4	19
2016 July	20	2	22
2016 June	83	11	94
2016 May	70	18	88
2016 April	58	28	86
2016 March	51	17	68
2016 February	57	16	73
2016 January	48	21	69
2015 December	52	12	64
2015 November	54	15	69
2015 October	65	16	81
2015 September	58	13	71
2015 August	71	15	86
2015 July	109	10	119
2015 June	57	14	71
2015 May	98	41	139
2015 April	75	18	93
2015 March	90	14	104
2015 February	70	24	94
2015 January	75	18	93
2014 December	45	12	57

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