Fármacos Insulinotrópicos para a Diabetes

Descrição Geral

Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus tipo 2

• Causada por:
  • Resistência periférica à insulina: os recetores celulares de insulina não respondem adequadamente à insulina.
  • Disfunção das células beta: ↑ necessidade de insulina a longo prazo → secreção de insulina defeituosa
• Resulta em hiperglicemia
• A abordagem farmacológica pode ter como alvo a:
  • Libertação de insulina
  • Resistência à insulina
  • Libertação de glucagon Glucagon A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal glucagon-like peptides. Glucagon is secreted by pancreatic alpha cells and plays an important role in regulation of blood glucose concentration, ketone metabolism, and several other biochemical and physiological processes. Gastrointestinal Secretions
  • Gliconeogénese
  • Absorção de glicose

Classificação

Os fármacos hipoglicemiantes podem ser classificados com base no seu mecanismo de ação:

Fármacos insulinotrópicos (↑ secreção de insulina):

• Sulfonilureias
• Meglitinidas
• Agonistas do péptido-1 semelhante ao glucagon Glucagon A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal glucagon-like peptides. Glucagon is secreted by pancreatic alpha cells and plays an important role in regulation of blood glucose concentration, ketone metabolism, and several other biochemical and physiological processes. Gastrointestinal Secretions ( GLP-1 GLP-1 A peptide of 36 or 37 amino acids that is derived from proglucagon and mainly produced by the intestinal l cells. Glp-1(1-37 or 1-36) is further n-terminally truncated resulting in glp-1(7-37) or glp-1-(7-36) which can be amidated. These glp-1 peptides are known to enhance glucose-dependent insulin release, suppress glucagon release and gastric emptying, lower blood glucose, and reduce food intake. Insulinomas, pela sigla em inglês)
• Inibidores da DPP-4

Fármacos não insulinotrópicos (não afetam a libertação de insulina):

• ↓ Resistência à insulina:
  • Biguanidas
  • Tiazolidinedionas
• ↓ Absorção/reabsorção de glicose:
  • Inibidores da alfa-glicosidase
  • Inibidores da proteína de transporte de sódio-glicose 2 (SGLT2, pela sigla em inglês)
• ↓ Esvaziamento gástrico e secreção de glucagon Glucagon A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal glucagon-like peptides. Glucagon is secreted by pancreatic alpha cells and plays an important role in regulation of blood glucose concentration, ketone metabolism, and several other biochemical and physiological processes. Gastrointestinal Secretions: análogos da amilina

Sulfonilureias

Fármacos da classe

• 1.ª geração:
  • Tolbutamida
  • Clorpropamida
  • Tolazamida
• 2.ª geração:
  • Gliburida
  • Glipizida
  • Glimepirida

Farmacodinâmica

• Liga-se e inibe os canais de potássio sensíveis ao ATP (ATPK) nas células beta pancreáticas
• Despolarização celular → abertura do canal de cálcio ( Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts) ²⁺) → influxo de Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts) ²⁺
• Estimula a libertação de insulina
• Resultado: ↑ capacidade de resposta das células beta à glicose
• Efeitos extra-pancreáticos:
  • ↑ Sensibilidade do tecido à insulina
  • ↓ Débito hepático de glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance

Farmacocinética

Descrição da farmacocinética das sulfonilureias de 2.ª geração:

• Absorção: boa absorção por via oral
• Distribuição: ligação extensa a proteínas
• Metabolismo:
  • Hepático via sistema do citocromo P450 ( CYP2C9 CYP2C9 A cytochrome p-450 subtype that has specificity for acidic xenobiotics. It oxidizes a broad range of important clinical drugs that fall under the categories of nonsteroidal anti-inflammatory agents; hypoglycemic agents; anticoagulants; and diuretics. Anticoagulants)
  • Metabolitos apresentam baixa atividade hipoglicemiante
• Excreção:
  • Principalmente na urina
  • Alguma excreção através das fezes

Indicações

As sulfonilureias são utilizadas no tratamento da diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus tipo 2:

• Geralmente usadas em combinação com outros fármacos
• Podem ser consideradas um agente de 1.ª linha em:
  • Contraindicações da metformina
  • Hiperglicemia grave sem cetonúria (se houver contraindicação à insulina ou análogos do GLP-1 GLP-1 A peptide of 36 or 37 amino acids that is derived from proglucagon and mainly produced by the intestinal l cells. Glp-1(1-37 or 1-36) is further n-terminally truncated resulting in glp-1(7-37) or glp-1-(7-36) which can be amidated. These glp-1 peptides are known to enhance glucose-dependent insulin release, suppress glucagon release and gastric emptying, lower blood glucose, and reduce food intake. Insulinomas)
• Não são usadas frequentemente devido aos seus efeitos adversos

Efeitos adversos

• Hipoglicemia
• Aumento de peso
• Náuseas
• Fotossensibilidade
• Hepatite
• Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types hemolítica
• Reações do tipo dissulfiram
• Reações de hipersensibilidade:
  • Erupção cutânea
  • Prurido

Contraindicações

• Hipersensibilidade às sulfonamidas
• Insuficiência hepática: fármacos que são metabolizados a nível hepático (pode levar à hipoglicemia)
• Insuficiência renal: excretada pelos rins (pode levar à hipoglicemia)
• Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus tipo 1
• Cetoacidose diabética

Interações farmacológicas

• Reação do tipo dissulfiram: etanol
• ↑ Efeito hipoglicemiante:
  • Outros fármacos antidiabéticos
  • Amiodarona
  • Androgénios
  • Betabloqueadores
  • Cloranfenicol
  • Antidepressivos
  • Antibióticos sulfonamidas

Meglitinidas

Fármacos da classe

• Repaglinida
• Nateglinida

Farmacodinâmica

• Estruturalmente diferentes, mas atuam de forma semelhante às sulfonilureias
• Afetam os canais ATPK nas células beta pancreáticas
• ↑ Libertação de insulina

Farmacocinética

• Absorção:
  • Rápida
  • Início de ação mais MAIS Androgen Insensitivity Syndrome rápido do que as sulfonilureias
• Distribuição:
  • Ligação extensa a proteínas
  • Duração de ação mais MAIS Androgen Insensitivity Syndrome curta do que as sulfonilureias
• Metabolismo:
  • Hepático
  • Via sistema do citocromo P450:
    • CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers)
    • CYP2C8 CYP2C8 A liver microsomal cytochrome p450 hydroxylase that oxidizes a broad spectrum of substrates including steroids, fatty acids, and xenobiotics. Examples of pharmaceutical substrates for cyp2c8 include; paclitaxol; torsemide; and; amodiaquine. Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers)
• Excreção:
  • Repaglinida: principalmente fezes
  • Nateglinida: principalmente urina

Indicações

As meglitinidas são utilizadas na diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus tipo 2:

• Em combinação com outros fármacos
• Em substituição de uma sulfonilureia em indivíduos com alergia
• Para controlo de hiperglicemia pós-prandial

Efeitos adversos

• Hipoglicemia
• Aumento de peso
• Infeções do trato respiratório
• Cefaleia

Contraindicações

• Insuficiência renal
• Insuficiência hepática
• Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus tipo 1
• Cetoacidose diabética

Interações farmacológicas

Um aumento do efeito hipoglicemiante pode ser observado com:

• Outros fármacos antidiabéticos
• Androgénios
• Agentes antivíricos de ação direta
• Gemfibrozil Gemfibrozil A lipid-regulating agent that lowers elevated serum lipids primarily by decreasing serum triglycerides with a variable reduction in total cholesterol. Lipid Control Drugs
• Estatinas
• Clopidogrel Clopidogrel A ticlopidine analog and platelet purinergic p2y receptor antagonist that inhibits adenosine diphosphate-mediated platelet aggregation. It is used to prevent thromboembolism in patients with arterial occlusive diseases; myocardial infarction; stroke; or atrial fibrillation. Antiplatelet Drugs
• Antidepressivos (por exemplo, inibidores seletivos da recaptação de serotonina, inibidores da monoamina oxidase Oxidase Neisseria)

Agonistas do Péptido-1 Semelhante ao Glucagon (GLP-1)

Fármacos da classe

• Exenatida (derivado do veneno do monstro de Gila)
• Liraglutida
• Dulaglutida
• Semaglutida
• Lixisenatida

Farmacodinâmica

• Incretino-miméticos (agonistas do GLP-1 GLP-1 A peptide of 36 or 37 amino acids that is derived from proglucagon and mainly produced by the intestinal l cells. Glp-1(1-37 or 1-36) is further n-terminally truncated resulting in glp-1(7-37) or glp-1-(7-36) which can be amidated. These glp-1 peptides are known to enhance glucose-dependent insulin release, suppress glucagon release and gastric emptying, lower blood glucose, and reduce food intake. Insulinomas) → ligam-se aos recetores do GLP-1 GLP-1 A peptide of 36 or 37 amino acids that is derived from proglucagon and mainly produced by the intestinal l cells. Glp-1(1-37 or 1-36) is further n-terminally truncated resulting in glp-1(7-37) or glp-1-(7-36) which can be amidated. These glp-1 peptides are known to enhance glucose-dependent insulin release, suppress glucagon release and gastric emptying, lower blood glucose, and reduce food intake. Insulinomas:
  • Células beta → ↑ secreção de insulina dependente de glicose
  • Células alfa → ↓ secreção de glucagon Glucagon A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal glucagon-like peptides. Glucagon is secreted by pancreatic alpha cells and plays an important role in regulation of blood glucose concentration, ketone metabolism, and several other biochemical and physiological processes. Gastrointestinal Secretions
• Efeitos adicionais:
  • Atraso do esvaziamento gástrico
  • ↓ Apetite
  • Perda de peso

Farmacocinética

• Absorção: administração por injeções subcutâneas
• Distribuição: ligação extensa a proteínas
• Excreção: urina e fezes

Indicações

• Tratamento da diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus tipo 2:
  • Não é um tratamento inicial para a maioria dos indivíduos
  • Frequentemente utilizado em combinação com outros fármacos
  • Associado a uma diminuição de eventos cardiovasculares
• Controlo do peso

Efeitos adversos

• Náuseas e vómitos
• Diarreia
• Pancreatite
• Trombocitopenia
• Lesão renal aguda
• Reações de hipersensibilidade:
  • Angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema
  • Anafilaxia
  • Reações no local da injeção

Contraindicações

• História pessoal ou familiar de carcinoma medular da tiroide (CMT) (estudos em animais mostram potencial associação a cancro da tiroide)
• Síndrome de neoplasia endócrina múltipla tipo 2 (MEN2)
• Distúrbios da motilidade GI devido ao atraso do esvaziamento GI
• História de pancreatite
• Insuficiência renal

Interações farmacológicas

• ↑ Efeito hipoglicemiante:
  • Outros fármacos antidiabéticos
  • Androgénios
  • Agentes antivíricos de ação direta
  • Antidepressivos
• O tratamento combinado com inibidores da DPP-4 não oferece benefícios adicionais.

Inibidores da Dipeptidil Peptidase-4 (DPP-4)

Fármacos da classe

• Sitagliptina
• Saxagliptina
• Linagliptina
• Alogliptina

Farmacodinâmica

• Inibição da enzima DPP-4, que normalmente degrada o GLP-1 GLP-1 A peptide of 36 or 37 amino acids that is derived from proglucagon and mainly produced by the intestinal l cells. Glp-1(1-37 or 1-36) is further n-terminally truncated resulting in glp-1(7-37) or glp-1-(7-36) which can be amidated. These glp-1 peptides are known to enhance glucose-dependent insulin release, suppress glucagon release and gastric emptying, lower blood glucose, and reduce food intake. Insulinomas
• ↑ Efeito das incretinas:
  • ↑ Secreção de insulina dependente de glicose
  • ↓ Níveis de glucagon Glucagon A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal glucagon-like peptides. Glucagon is secreted by pancreatic alpha cells and plays an important role in regulation of blood glucose concentration, ketone metabolism, and several other biochemical and physiological processes. Gastrointestinal Secretions

Farmacocinética

• Absorção: via oral
• Distribuição:
  • Extensa
  • Ligação a proteínas variável
• Metabolismo:
  • Variável
  • Hepático
  • Alguns pelo sistema do citocromo P450
• Excreção:
  • Principalmente pela urina
  • Exceção: A linagliptina é excretada principalmente pelas fezes.

Indicações

Os inibidores da DPP-4 são utilizados no tratamento da diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus tipo 2:

• Não são um tratamento inicial para a maioria dos indivíduos
• Utilizados como tratamento adjuvante

Efeitos adversos

• Nasofaringite e infeções do trato respiratório superior
• Cefaleias
• Artralgias e mialgias
• Pancreatite aguda
• Disfunção hepática
• Penfigoide bolhoso
• Insuficiência cardíaca
• Reações de hipersensibilidade:
  • Angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema
  • Anafilaxia
  • Urticária

Contraindicações

• Insuficiência renal
• Insuficiência hepática
• Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus tipo 1
• Cetoacidose diabética

Interações farmacológicas

• ↑ Efeito hipoglicemiante:
  • Outros fármacos antidiabéticos
  • Androgénios
  • Agentes antivíricos de ação direta
  • Antidepressivos
• ↑ Toxicidade de:
  • Inibidores da ECA
  • Digoxina
• O tratamento combinado com agonistas do GLP-1 GLP-1 A peptide of 36 or 37 amino acids that is derived from proglucagon and mainly produced by the intestinal l cells. Glp-1(1-37 or 1-36) is further n-terminally truncated resulting in glp-1(7-37) or glp-1-(7-36) which can be amidated. These glp-1 peptides are known to enhance glucose-dependent insulin release, suppress glucagon release and gastric emptying, lower blood glucose, and reduce food intake. Insulinomas não oferece benefícios adicionais.

Comparação de Fármacos Antidiabéticos

A tabela seguinte compara fármacos não insulínicos para o tratamento da diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus tipo 2:

Os efeitos dos fármacos para a diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus no peso podem ser um fator na escolha do tratamento de um indivíduo:

• Perda de peso:
  • Agonistas do GLP-1 GLP-1 A peptide of 36 or 37 amino acids that is derived from proglucagon and mainly produced by the intestinal l cells. Glp-1(1-37 or 1-36) is further n-terminally truncated resulting in glp-1(7-37) or glp-1-(7-36) which can be amidated. These glp-1 peptides are known to enhance glucose-dependent insulin release, suppress glucagon release and gastric emptying, lower blood glucose, and reduce food intake. Insulinomas
  • Inibidores da SGLT2
• Efeito neutro no peso:
  • Inibidores da alfa-glicosidase
  • Inibidores da DPP-4
• Ganho de peso:
  • Insulina
  • Sulfonilureias
  • Tiazolidinedionas
  • Meglitinidas