Background: Inappropriate use of medications (IUM), in particular inappropriate prescribing and non-adherence to prescribed medications, are important causes of drug-related morbidities (DRMs). They are increasing problems with the ageing populations and the growing burden of chronic conditions. However, research is needed on the association of IUMs with DRMs in outpatient settings and in the general population. Aim: The aim of this thesis is to estimate and analyse the burden of potentially inappropriate prescriptions (PIPs) in the elderly and non-adherence to long-term medications among adults across care settings, and to investigate how IUM is associated to DRMs. Methods: A meta-analysis summarised the previous evidence on the percentage of adverse drug reactions (ADRs) associated to IUM across healthcare settings (Study I). From a cohort in the general population, using medical records and register data, the prevalence of PIPs in the elderly and its association with ADRs were estimated retrospectively (Study II). From the same cohort, the factors associated with refill non-adherence to antihypertensive therapy, considering the use of multiple medications, and the association between non-adherence and sub-therapeutic effects (STEs) were investigated (Study III). A survey assessed the refill behaviour to antihypertensive, lipid lowering and oral antidiabetic medications (undersupply, adequate supply and oversupply), and its association with perceived ADRs and STEs (Study IV). Results: IUM was the cause 52% and 45% of ADRs occurring in adult outpatients and inpatients respectively. Across healthcare settings, 46% of the elderly refilled PIPs over a 6-month period; PIPs were considered the cause of 30% of all ADRs; and the elderly who were prescribed PIPs had increased odds to experience ADRs (OR 2.47, 95% CI 1.65-3.69). In total, 35% was nonadherent to the full multidrug therapy and 13% was non-adherent to any medication (complete non-adherence).  Sociodemographic factors (working age and lower income) were associated with non-adherence to any medication, while clinical factors (use of specialised care, use of multiple medications, and being a new user) with non-adherence to the full multidrug therapy. STEs were associated with non-adherence to any medication a month prior to a healthcare visit (OR 3.27, 95% CI 1.27-8.49), but not with long-term measures of non-adherence. Among survey respondents, 22% of the medications were oversupplied and 12% were undersupplied. Inadequate refill behaviour was not associated with reporting ADRs or STEs (p<0.05). Conclusions: A large proportion of ADRs occurring in hospital is caused by IUM, but more knowledge is needed in other settings. PIPs are common in the elderly general population and associated with ADRs. Therefore decreasing PIPs could contribute towards ADR prevention. Considering the use of multiple medications may help to better understand the factors associated with non-adherence to a multidrug therapy for tailoring the interventions to patient needs. Monitoring the adherence prior to a healthcare visit may facilitate interpreting STEs. Yet, the absence of an association between long-term measures of refill non-adherence with clinical and perceived DRMs suggest the need to enhance the knowledge of this association in clinical practice. In summary, this thesis shows a significant potential for improvements of medication use and outcomes.

Introdução: As morbidades e mortalidade relacionadas ao uso de medicamentos (MRM) representam um desafio para a saúde pública e são consequências da utilização não efetiva e insegura dos medicamentos. Estudos internacionais mostram como as MRM afetam pacientes internados no hospital e como podem ser evitadas na maioria dos casos. Entretanto, pouco é conhecido sobre as MRM na prática ambulatorial. Estas pesquisas têm abordado as consequências clínicas negativas para os usuários de medicamentos e sugerem que vultosas somas de recursos financeiros são utilizadas para manejar e resolver estas morbidades ao redor do mundo. Já no Brasil, o conhecimento sobre as MRM é escasso em ambas perspectivas e o seu impacto econômico é desconhecido. Objetivo: O propósito desta Tese foi obter uma estimativa sobre os gastos com morbidade e mortalidade associadas ao uso de medicamentos no Brasil, utilizando modelos farmacoeconômicos (teórico e empírico). Métodos: Foram considerados como morbidades relacionadas a medicamentos os novos problemas de saúde advindos da utilização de uma farmacoterapia (por exemplo, reações adversas, dependência a medicamentos e intoxicação por overdose) e as falhas terapêuticas (por exemplo, efeito insuficiente dos medicamentos e problemas de saúde não tratados). Foram conduzidos dois estudos utilizando abordagens distintas (bottom up e top down) na coleta de dados sobre custos. O primeiro estimou, por meio da análise do tipo microcosting, os custos para resolução de Morbidades Relacionadas a Medicamentos em casos identificados no serviço de emergência de um hospital universitário. Resultados: O custo médio para tratar cada um desses pacientes é de aproximadamente R$ 2.200. Reações adversas a medicamentos, falta de adesão à farmacoterapia e problemas resultantes da administração de doses incorretas foram as causas mais prevalentes das morbidades. No segundo estudo, um modelo do tipo cost-of-illness foi traduzido e adaptado para a realidade brasileira, e então um painel com especialistas (farmacêuticos e médicos) foi realizado para estimar a proporção de pacientes que experimentam uma MRM, a proporção de MRM evitáveis e as consequências clínicas resultantes desta morbidade. A partir disto, o custo das MRM para o sistema de saúde brasileiro foi modelado, baseado em estatísticas nacionais sobre o consumo de serviços de saúde. Os especialistas julgaram as morbidades relacionadas a medicamentos como um evento bastante frequente. De acordo com esta estimativa central, as MRM seriam responsáveis por um uso considerável de recursos, podendo chegar a 23% do orçamento público anual total destinado à saúde no Brasil. Para cada real gasto com medicamentos, pelo Ministério da Saúde no Brasil, cinco reais seriam gastos para resolver as MRM. Da mesma forma foi verificado que mais da metade dos casos seriam evitáveis. Conclusão: As MRM são, de fato, um problema de ordem econômica-orçamentária, clínica e humanística para os usuários de medicamentos e para o sistema de saúde brasileiro, e que é imperiosa a criação de políticas públicas e ações capazes de evitar os danos gerados pelo uso não racional de medicamentos, garantir a segurança dos pacientes, bem como uma melhor alocação de recursos em saúde. / Introduction: Drug related morbidities and mortality (DRM) is a challenge to public health due to the consequences of ineffective and unsafe medicines use. It is well known that the DRM are common among hospitalized patients, and are preventable to some extent, but little is known about DRM outside the hospital. In Brazil, the knowledge on the subject is scarce and its economic impact is unknown. However, international studies suggest that DRM result in considerable amounts of financial resources to manage and resolve these morbidities around the world and the negative clinical consequences for those who use medicines. Aim: In this thesis, the drug related morbidities include: new medical problems arising from the pharmacotherapy (adverse effects, addiction to drugs and intoxication by overdose) and therapeutic failure (e.g. insufficient drug effect and untreated health problems). Methods: Two studies were conducted using different methodologies. The first study was a cross-sectional study, based on a microcosting analysis, where patients admitted to a teaching hospital emergency were identified in order to determine the proportion of people seeking health services due to a DRM, and, consequently, to obtain the cost for manage these patients. Results: It was observed that 14.6% of patients visiting an emergency service, do so because of a DRM and the average cost to treat each of these patients is approximately R$ 2,000. Adverse drug reactions, lack of adherence to pharmacotherapy and problems resulting from the administration of incorrect doses were the most prevalent causes of morbidity. In the second study, a cost-of-illness model was translated to portuguese and adapted, and then a panel of experts (pharmacists and physicians) was conducted to estimate the proportion of patients experiencing DRM, the proportion of preventable DRM, and the negative outcomes resulting from this morbidity. From this, the DRM cost for the Brazilian Health System was modeled, based on national statistics on the consumption of health services. Experts have judged drug-related morbidities to be a fairly frequent event. According to central estimate, the DRM would be responsible for a considerable use of resources, being able to reach 23% of the total annual public health budget in Brazil. For each real (R$ 1,00) spending on medicines, by the Brazilian Ministry of Health, five reais (R$ 5,00) would be spent to manage the DRM. Likewise, in this study it was also verified that more than half of the cases would be avoidable. In the second, a panel of experts (pharmacists and physicians) was performed to estimate the proportion of patients experiencing an DRM, DRM preventable ratio and the clinical consequences of this morbidity. From this, the cost of DRM for the Brazilian health system was modeled, based on national statistics on the consumption of health services. Conclusion: Based on these and many other results presented in this thesis, it is concluded that the DRM are indeed, an economic, clinical and humanistic issue for those who use medicines and to the Brazilian health system, and that is overriding the establishment of public policies and actions to prevent the damage caused by the non-rational use of medicines to ensure patient safety and to the best allocation of health resources.

Introdução: As morbidades e mortalidade relacionadas ao uso de medicamentos (MRM) representam um desafio para a saúde pública e são consequências da utilização não efetiva e insegura dos medicamentos. Estudos internacionais mostram como as MRM afetam pacientes internados no hospital e como podem ser evitadas na maioria dos casos. Entretanto, pouco é conhecido sobre as MRM na prática ambulatorial. Estas pesquisas têm abordado as consequências clínicas negativas para os usuários de medicamentos e sugerem que vultosas somas de recursos financeiros são utilizadas para manejar e resolver estas morbidades ao redor do mundo. Já no Brasil, o conhecimento sobre as MRM é escasso em ambas perspectivas e o seu impacto econômico é desconhecido. Objetivo: O propósito desta Tese foi obter uma estimativa sobre os gastos com morbidade e mortalidade associadas ao uso de medicamentos no Brasil, utilizando modelos farmacoeconômicos (teórico e empírico). Métodos: Foram considerados como morbidades relacionadas a medicamentos os novos problemas de saúde advindos da utilização de uma farmacoterapia (por exemplo, reações adversas, dependência a medicamentos e intoxicação por overdose) e as falhas terapêuticas (por exemplo, efeito insuficiente dos medicamentos e problemas de saúde não tratados). Foram conduzidos dois estudos utilizando abordagens distintas (bottom up e top down) na coleta de dados sobre custos. O primeiro estimou, por meio da análise do tipo microcosting, os custos para resolução de Morbidades Relacionadas a Medicamentos em casos identificados no serviço de emergência de um hospital universitário. Resultados: O custo médio para tratar cada um desses pacientes é de aproximadamente R$ 2.200. Reações adversas a medicamentos, falta de adesão à farmacoterapia e problemas resultantes da administração de doses incorretas foram as causas mais prevalentes das morbidades. No segundo estudo, um modelo do tipo cost-of-illness foi traduzido e adaptado para a realidade brasileira, e então um painel com especialistas (farmacêuticos e médicos) foi realizado para estimar a proporção de pacientes que experimentam uma MRM, a proporção de MRM evitáveis e as consequências clínicas resultantes desta morbidade. A partir disto, o custo das MRM para o sistema de saúde brasileiro foi modelado, baseado em estatísticas nacionais sobre o consumo de serviços de saúde. Os especialistas julgaram as morbidades relacionadas a medicamentos como um evento bastante frequente. De acordo com esta estimativa central, as MRM seriam responsáveis por um uso considerável de recursos, podendo chegar a 23% do orçamento público anual total destinado à saúde no Brasil. Para cada real gasto com medicamentos, pelo Ministério da Saúde no Brasil, cinco reais seriam gastos para resolver as MRM. Da mesma forma foi verificado que mais da metade dos casos seriam evitáveis. Conclusão: As MRM são, de fato, um problema de ordem econômica-orçamentária, clínica e humanística para os usuários de medicamentos e para o sistema de saúde brasileiro, e que é imperiosa a criação de políticas públicas e ações capazes de evitar os danos gerados pelo uso não racional de medicamentos, garantir a segurança dos pacientes, bem como uma melhor alocação de recursos em saúde. / Introduction: Drug related morbidities and mortality (DRM) is a challenge to public health due to the consequences of ineffective and unsafe medicines use. It is well known that the DRM are common among hospitalized patients, and are preventable to some extent, but little is known about DRM outside the hospital. In Brazil, the knowledge on the subject is scarce and its economic impact is unknown. However, international studies suggest that DRM result in considerable amounts of financial resources to manage and resolve these morbidities around the world and the negative clinical consequences for those who use medicines. Aim: In this thesis, the drug related morbidities include: new medical problems arising from the pharmacotherapy (adverse effects, addiction to drugs and intoxication by overdose) and therapeutic failure (e.g. insufficient drug effect and untreated health problems). Methods: Two studies were conducted using different methodologies. The first study was a cross-sectional study, based on a microcosting analysis, where patients admitted to a teaching hospital emergency were identified in order to determine the proportion of people seeking health services due to a DRM, and, consequently, to obtain the cost for manage these patients. Results: It was observed that 14.6% of patients visiting an emergency service, do so because of a DRM and the average cost to treat each of these patients is approximately R$ 2,000. Adverse drug reactions, lack of adherence to pharmacotherapy and problems resulting from the administration of incorrect doses were the most prevalent causes of morbidity. In the second study, a cost-of-illness model was translated to portuguese and adapted, and then a panel of experts (pharmacists and physicians) was conducted to estimate the proportion of patients experiencing DRM, the proportion of preventable DRM, and the negative outcomes resulting from this morbidity. From this, the DRM cost for the Brazilian Health System was modeled, based on national statistics on the consumption of health services. Experts have judged drug-related morbidities to be a fairly frequent event. According to central estimate, the DRM would be responsible for a considerable use of resources, being able to reach 23% of the total annual public health budget in Brazil. For each real (R$ 1,00) spending on medicines, by the Brazilian Ministry of Health, five reais (R$ 5,00) would be spent to manage the DRM. Likewise, in this study it was also verified that more than half of the cases would be avoidable. In the second, a panel of experts (pharmacists and physicians) was performed to estimate the proportion of patients experiencing an DRM, DRM preventable ratio and the clinical consequences of this morbidity. From this, the cost of DRM for the Brazilian health system was modeled, based on national statistics on the consumption of health services. Conclusion: Based on these and many other results presented in this thesis, it is concluded that the DRM are indeed, an economic, clinical and humanistic issue for those who use medicines and to the Brazilian health system, and that is overriding the establishment of public policies and actions to prevent the damage caused by the non-rational use of medicines to ensure patient safety and to the best allocation of health resources.

Introdução: As morbidades e mortalidade relacionadas ao uso de medicamentos (MRM) representam um desafio para a saúde pública e são consequências da utilização não efetiva e insegura dos medicamentos. Estudos internacionais mostram como as MRM afetam pacientes internados no hospital e como podem ser evitadas na maioria dos casos. Entretanto, pouco é conhecido sobre as MRM na prática ambulatorial. Estas pesquisas têm abordado as consequências clínicas negativas para os usuários de medicamentos e sugerem que vultosas somas de recursos financeiros são utilizadas para manejar e resolver estas morbidades ao redor do mundo. Já no Brasil, o conhecimento sobre as MRM é escasso em ambas perspectivas e o seu impacto econômico é desconhecido. Objetivo: O propósito desta Tese foi obter uma estimativa sobre os gastos com morbidade e mortalidade associadas ao uso de medicamentos no Brasil, utilizando modelos farmacoeconômicos (teórico e empírico). Métodos: Foram considerados como morbidades relacionadas a medicamentos os novos problemas de saúde advindos da utilização de uma farmacoterapia (por exemplo, reações adversas, dependência a medicamentos e intoxicação por overdose) e as falhas terapêuticas (por exemplo, efeito insuficiente dos medicamentos e problemas de saúde não tratados). Foram conduzidos dois estudos utilizando abordagens distintas (bottom up e top down) na coleta de dados sobre custos. O primeiro estimou, por meio da análise do tipo microcosting, os custos para resolução de Morbidades Relacionadas a Medicamentos em casos identificados no serviço de emergência de um hospital universitário. Resultados: O custo médio para tratar cada um desses pacientes é de aproximadamente R$ 2.200. Reações adversas a medicamentos, falta de adesão à farmacoterapia e problemas resultantes da administração de doses incorretas foram as causas mais prevalentes das morbidades. No segundo estudo, um modelo do tipo cost-of-illness foi traduzido e adaptado para a realidade brasileira, e então um painel com especialistas (farmacêuticos e médicos) foi realizado para estimar a proporção de pacientes que experimentam uma MRM, a proporção de MRM evitáveis e as consequências clínicas resultantes desta morbidade. A partir disto, o custo das MRM para o sistema de saúde brasileiro foi modelado, baseado em estatísticas nacionais sobre o consumo de serviços de saúde. Os especialistas julgaram as morbidades relacionadas a medicamentos como um evento bastante frequente. De acordo com esta estimativa central, as MRM seriam responsáveis por um uso considerável de recursos, podendo chegar a 23% do orçamento público anual total destinado à saúde no Brasil. Para cada real gasto com medicamentos, pelo Ministério da Saúde no Brasil, cinco reais seriam gastos para resolver as MRM. Da mesma forma foi verificado que mais da metade dos casos seriam evitáveis. Conclusão: As MRM são, de fato, um problema de ordem econômica-orçamentária, clínica e humanística para os usuários de medicamentos e para o sistema de saúde brasileiro, e que é imperiosa a criação de políticas públicas e ações capazes de evitar os danos gerados pelo uso não racional de medicamentos, garantir a segurança dos pacientes, bem como uma melhor alocação de recursos em saúde. / Introduction: Drug related morbidities and mortality (DRM) is a challenge to public health due to the consequences of ineffective and unsafe medicines use. It is well known that the DRM are common among hospitalized patients, and are preventable to some extent, but little is known about DRM outside the hospital. In Brazil, the knowledge on the subject is scarce and its economic impact is unknown. However, international studies suggest that DRM result in considerable amounts of financial resources to manage and resolve these morbidities around the world and the negative clinical consequences for those who use medicines. Aim: In this thesis, the drug related morbidities include: new medical problems arising from the pharmacotherapy (adverse effects, addiction to drugs and intoxication by overdose) and therapeutic failure (e.g. insufficient drug effect and untreated health problems). Methods: Two studies were conducted using different methodologies. The first study was a cross-sectional study, based on a microcosting analysis, where patients admitted to a teaching hospital emergency were identified in order to determine the proportion of people seeking health services due to a DRM, and, consequently, to obtain the cost for manage these patients. Results: It was observed that 14.6% of patients visiting an emergency service, do so because of a DRM and the average cost to treat each of these patients is approximately R$ 2,000. Adverse drug reactions, lack of adherence to pharmacotherapy and problems resulting from the administration of incorrect doses were the most prevalent causes of morbidity. In the second study, a cost-of-illness model was translated to portuguese and adapted, and then a panel of experts (pharmacists and physicians) was conducted to estimate the proportion of patients experiencing DRM, the proportion of preventable DRM, and the negative outcomes resulting from this morbidity. From this, the DRM cost for the Brazilian Health System was modeled, based on national statistics on the consumption of health services. Experts have judged drug-related morbidities to be a fairly frequent event. According to central estimate, the DRM would be responsible for a considerable use of resources, being able to reach 23% of the total annual public health budget in Brazil. For each real (R$ 1,00) spending on medicines, by the Brazilian Ministry of Health, five reais (R$ 5,00) would be spent to manage the DRM. Likewise, in this study it was also verified that more than half of the cases would be avoidable. In the second, a panel of experts (pharmacists and physicians) was performed to estimate the proportion of patients experiencing an DRM, DRM preventable ratio and the clinical consequences of this morbidity. From this, the cost of DRM for the Brazilian health system was modeled, based on national statistics on the consumption of health services. Conclusion: Based on these and many other results presented in this thesis, it is concluded that the DRM are indeed, an economic, clinical and humanistic issue for those who use medicines and to the Brazilian health system, and that is overriding the establishment of public policies and actions to prevent the damage caused by the non-rational use of medicines to ensure patient safety and to the best allocation of health resources.