Nitroimidazois

Estrutura Química e Farmacodinâmica

Estrutura química

Os nitroimidazois são compostos por um anel imidazol e um grupo nitro anexado.

Mecanismo de ação

• Os nitroimidazois difundem-se passivamente na célula microbiana.
• Nitroredutases (produzidas por organismos suscetíveis) → reduzem o grupo nitro na molécula ativando-a
• Resulta na produção de:
  • Radicais livres
  • Metabolitos citotóxicos → interagem com o DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure bacteriano → quebra da cadeia de DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure e desestabilização
• Ocorre morte celular.
• Efeito:
  • Bactericida contra bactérias anaeróbias
  • Antiprotozoário

Farmacocinética

O seguinte descreve a farmacocinética do metronidazol (o fármaco padrão desta classe) e do tinidazol.

Absorção

• Quase completamente absorvido quando administrado por via oral
• Biodisponibilidade > 90%

Distribuição

• Distribuído amplamente em tecidos
• Baixa ligação às proteínas (< 20%)
• Ultrapassa a barreira hematoencefálica

Metabolismo e excreção

• Extensamente metabolizado no fígado
• Excretado principalmente na urina

Indicações

Cobertura antimicrobiana

• Bactérias anaeróbias:
  • Helicobacter pylori Helicobacter pylori A spiral bacterium active as a human gastric pathogen. It is a gram-negative, urease-positive, curved or slightly spiral organism initially isolated in 1982 from patients with lesions of gastritis or peptic ulcers in Western Australia. Helicobacter pylori was originally classified in the genus campylobacter, but RNA sequencing, cellular fatty acid profiles, growth patterns, and other taxonomic characteristics indicate that the micro-organism should be included in the genus Helicobacter. It has been officially transferred to Helicobacter gen. Helicobacter
  • Bacteroides Bacteroides Bacteroides is a genus of opportunistic, anaerobic, gram-negative bacilli. Bacteroides fragilis is the most common species involved in human disease and is part of the normal flora of the large intestine. Bacteroides
  • Clostridium (incluindo C. difficile)
  • Gardnerella Gardnerella A genus of bacteria found in the human genital and urinary tract. It is considered to be a major cause of bacterial vaginosis. Nitroimidazoles
• Protozoários:
  • Giardia Giardia A genus of flagellate intestinal eukaryotes parasitic in various vertebrates, including humans. Characteristics include the presence of four pairs of flagella arising from a complicated system of axonemes and cysts that are ellipsoidal to ovoidal in shape. Nitroimidazoles
  • Entamoeba Entamoeba A genus of ameboid protozoa characterized by the presence of beaded chromatin on the inner surface of the nuclear membrane. Its organisms are parasitic in invertebrates and vertebrates, including humans. Nitroimidazoles
  • Trichomonas Trichomonas A genus of parasitic flagellate eukaryotes distinguished by the presence of four anterior flagella, an undulating membrane, and a trailing flagellum. Nitroimidazoles

Tipos de infeção

• Colite pseudomembranosa
• Infeções ginecológicas (incluindo vaginose bacteriana)
• Amebíase
• Uretrite não-gonocócica
• Infeções intra-abdominais
• Abcesso intracraniano

Efeitos Adversos e Contraindicações

Efeitos adversos

• Distúrbios GI
• Reação semelhante ao dissulfiram com o álcool (devido à inibição da aldeído desidrogenase)
• Disgeusia (gosto metálico)
• Neuropatia periférica
• Cefaleias
• Tonturas
• Convulsões
• Descoloração da urina (cor castanho-avermelhada)

Contraindicações

• Gravidez (1º trimestre)
• Amamentação
• Insuficiência hepática grave

Interações medicamentosas

• Elixires contendo etanol:
  • Xaropes para a tosse
  • Trimetroprim-sulfametoxazol IV
• Dissulfiram: pode causar psicose aguda
• ↓ Eliminação de:
  • Lítio
  • Cravagem-do-centeio
• ↓ Metabolismo hepático de:
  • Fenitoína
  • Varfarina
  • Carbamazepina

Mecanismos de Resistência

A resistência ao metronidazol é rara, mas pode ocorrer por:

• ↓ Taxa de redução do metronidazol dentro dos anaeróbios
• ↓ Absorção do fármaco
• ↑ Efluxo do fármaco da célula
• ↑ Atividade da LDH LDH Osteosarcoma
• ↑ Atividade de enzimas de reparação do DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure
• ↑ Recursos para eliminação de oxigénio

Comparação de Antibióticos

A tabela a seguir compara várias classes de antibióticos com cobertura anaeróbia: