QUINOLONAS, FLUOROQUINOLONAS, y como evolucionaron..!! completo, FARMACOLOGÍA |PARTE 1

Introduction to DNA Synthesis Inhibitors

Overview of the Video

• David Vargas introduces the topic of DNA synthesis inhibitors, specifically focusing on quinolones and fluoroquinolones.

• Emphasizes a sophisticated approach by using "DNA" instead of "ADN."

Key Classifications

• The most significant groups discussed are quinolones and fluoroquinolones, with an emphasis on their clinical applications in urinary tract infections and potential side effects.

• A comprehensive overview is promised, highlighting important aspects for better retention during exams.

Mechanism of Action

Inhibition Process

• Quinolones inhibit DNA synthesis primarily by targeting topoisomerase II and IV, crucial enzymes in bacterial replication.

• Fluoroquinolones affect both topoisomerase II and IV, while traditional quinolones only inhibit topoisomerase II. This distinction is critical for understanding their bactericidal properties.

Bactericidal Effects

• The inability to synthesize new DNA leads to bactericidal effects, resulting in a post-antibiotic effect where the drug continues to work after administration.

Resistance Mechanisms

Key Resistance Factors

• The primary mechanism of resistance involves modifications at the action site due to mutations or plasmid acquisition. Other factors include decreased permeability and efflux pumps that expel the drug from bacterial cells.

Pharmacokinetics

Administration and Absorption

• Quinolones can be administered orally with excellent absorption rates (50% - 100%). However, they should not be taken with metal ions as this reduces absorption efficiency.

Distribution Characteristics

• These drugs effectively penetrate various tissues, including intracellular spaces, making them suitable for treating atypical infections caused by intracellular bacteria. However, penetration into cerebrospinal fluid varies among different quinolone types; for instance, ofloxacin has good CNS penetration.

Safety Profile and Side Effects

Contraindications

• Quinolones are contraindicated in pregnant women due to risks of genetic alterations and malformations (classified as category C).

Common Adverse Effects

• Notable side effects include confusion syndrome, tendinitis (especially affecting Achilles tendon), hallucinations, prolonged QT interval, photosensitivity reactions, Stevens-Johnson syndrome among others. Gastrointestinal disturbances are also common adverse effects noted in practice.

Clinical Indications

Spectrum of Activity

• Quinolones serve as alternatives to penicillins for urinary tract infections and can be used prophylactically as antiseptics across various generations based on their spectrum of activity against different pathogens like respiratory infections or gastrointestinal issues.

Generational Differences

• Each generation expands its indications: second-generation focuses on soft tissue infections; third-generation targets acute respiratory infections; fourth-generation is more specific towards anaerobes and certain severe bacterial conditions such as tuberculosis in neutropenic patients due to its broad spectrum capabilities.

Fluoroquinolones: Generations and Applications

Overview of Fluoroquinolone Generations

• The discussion begins with a comparison between ancient and modern fluoroquinolones, highlighting the classification into first, second, third, and fourth generations based on structural modifications.

• First-generation fluoroquinolones are mentioned as less commonly used in developing countries due to limited availability and effectiveness.

• Emphasis is placed on the importance of understanding these drugs for practical applications in saving lives.

Key Characteristics of Each Generation

• Second-generation fluoroquinolones like ciprofloxacin are crucial for treating infections; they have improved efficacy against gram-negative bacilli.

• Third (e.g., levofloxacin) and fourth-generation (e.g., moxifloxacin) fluoroquinolones are noted for their broader spectrum of activity, including respiratory indications.

Spectrum of Activity

• The evolution from first to fourth generation shows significant improvements in antimicrobial spectrum and pharmacokinetics.

• First-generation fluoroquinolones primarily target gram-negative bacilli but face resistance issues; thus, their clinical use has diminished.

• Second-generation agents expand coverage to include Pseudomonas aeruginosa, which is known for its intrinsic antibiotic resistance.

Advancements in Coverage

• Third and fourth generations enhance coverage against both gram-positive cocci and atypical intracellular infections such as mycobacteria.

• The limitations of earlier generations necessitated advancements that allow newer drugs to effectively treat more complex infections.

Specific Indications and Interactions

• Third-generation fluoroquinolones are effective against respiratory tract infections while fourth-generation agents uniquely cover anaerobes.

• A clear hierarchy is established where each subsequent generation covers the previous ones while adding new capabilities.

• Important interactions with other medications (e.g., warfarin, methylxanthines), particularly how certain cations can reduce quinolone concentrations, will be discussed later.

Conclusion & Further Learning

• The speaker encourages viewers not to miss upcoming slides that delve deeper into antimicrobial action spectra.

Introduction to the Video

Greetings and Audience Engagement

• The video is dedicated to viewers from Peru, with a call for comments indicating their country of origin. This helps in classifying responses and selecting future winners for giveaways.

• Acknowledgment of messages received from fans on Instagram and YouTube, including greetings from Bolivia and specific institutions like Universidad San Martín de Trujillo.

Overview of Quinolones and Fluoroquinolones

Mechanism of Action

• Introduction to quinolones, specifically fluoroquinolones, starting with the historical context of chloroquine's development into nalidixic acid, which treats infections caused by Gram-negative bacteria.

• Nalidixic acid features two rings and a carboxylic acid group that contributes to its antibacterial properties by inhibiting DNA synthesis through binding mechanisms.

Development of Fluoroquinolones

• The addition of fluorine atoms in fluoroquinolones enhances their spectrum of activity and penetration capabilities against various bacterial strains. This modification allows them to block topoisomerase IV effectively.

• Historical timeline:

• 1962: Introduction of nalidixic acid.

• 1978: Emergence of norfloxacin.

• 1990: Levofloxacin introduced.

• 2000: Further developments in fluoroquinolone drugs are noted.

Mechanisms Involving Topoisomerases

Role in Bacterial DNA Replication

• Discussion on how topoisomerase II (also known as DNA gyrase) facilitates the relaxation necessary for bacterial DNA replication by cutting and rejoining strands during supercoiling processes. This enzyme is crucial for maintaining DNA structure during cell division.

DNA Replication and Enzyme Functionality

Overview of DNA Polymerase and Topoisomerase

• The process begins with DNA polymerase, which copies the DNA strand, resulting in two daughter strands: one leading (pluma) and one lagging (naranja).

• After replication, the daughter strands remain connected, necessitating separation for the formation of new bacterial cells. This is where topoisomerase 2 comes into play.

• Topoisomerase 2 is crucial as it cuts and rejoins the DNA strands to facilitate their separation, allowing for the creation of two distinct bacterial daughters.

Impact of Fluoroquinolones on Bacterial Cells

• Fluoroquinolones are antibiotics that penetrate bacterial membranes and target topoisomerase 2, inhibiting its function.