Fluoroquinolones Overview
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Questions and Answers

What type of drugs are quinolones?

Synthetic antibacterials

What was the first quinolone drug?

Nalidixic acid

What are the primary targets of fluoroquinolones?

DNA gyrase (topoisomerase 2) and topoisomerase 4

What is the mechanism of action of fluoroquinolones?

<p>They bind to DNA gyrase and topoisomerase 4, interfering with DNA ligation and causing DNA breakage.</p> Signup and view all the answers

What is the role of DNA gyrase in DNA replication?

<p>It reduces torsional stress ahead of replicating forks by breaking double-strand DNA and introducing negative supercoils.</p> Signup and view all the answers

What is the role of topoisomerase IV in DNA replication?

<p>It assists in separating daughter chromosomes once replication is completed.</p> Signup and view all the answers

Fluoroquinolones have a high affinity for mammalian topoisomerase II.

<p>False (B)</p> Signup and view all the answers

Which of the following fluoroquinolones is a first-generation drug?

<p>Nalidixic acid (B)</p> Signup and view all the answers

Which of the following fluoroquinolones is a second-generation drug?

<p>Ciprofloxacin (B)</p> Signup and view all the answers

What is the primary route of administration for most fluoroquinolones?

<p>Oral</p> Signup and view all the answers

What are some factors that can interfere with the absorption of fluoroquinolones?

<p>Iron, zinc, and calcium (divalent cations)</p> Signup and view all the answers

Dosage adjustments are always required for fluoroquinolones in patients with renal dysfunction.

<p>False (B)</p> Signup and view all the answers

Where do fluoroquinolones accumulate in the body?

<p>Macrophages and polymorphonuclear leukocytes</p> Signup and view all the answers

Which of the following is NOT a common adverse effect of fluoroquinolones?

<p>Hypotension (C)</p> Signup and view all the answers

What are some common connective tissue problems associated with fluoroquinolones?

<p>Tendonitis and tendon rupture</p> Signup and view all the answers

What are some common superinfections associated with fluoroquinolones?

<p>C. difficile, C. albicans, and streptococci</p> Signup and view all the answers

What are two common drug-drug interactions associated with fluoroquinolones?

<p>Quinolones with theophylline and quinolones with warfarin</p> Signup and view all the answers

Folic acid is essential for the synthesis of DNA, RNA, and certain amino acids.

<p>True (A)</p> Signup and view all the answers

What is the critical folate derivative synthesized by humans?

<p>Tetrahydrofolic acid</p> Signup and view all the answers

Bacteria are generally permeable to folate derivatives.

<p>False (B)</p> Signup and view all the answers

When were sulfa drugs first used in clinical practice?

<p>They were among the first antibiotics used.</p> Signup and view all the answers

Why are sulfa drugs seldom prescribed alone today?

<p>Due to widespread resistance.</p> Signup and view all the answers

What is the primary mechanism of action of sulfonamides?

<p>They inhibit dihydrofolate synthase.</p> Signup and view all the answers

What is the metabolic pathway that sulfonamides interfere with?

<p>The synthesis of tetrahydrofolic acid</p> Signup and view all the answers

Sulfonamides can be given by intravenous injection.

<p>True (A)</p> Signup and view all the answers

What is the primary route of excretion of sulfonamides?

<p>Renal excretion</p> Signup and view all the answers

What is a common adverse effect of sulfonamides?

<p>Crystalluria</p> Signup and view all the answers

Which of the following is a common superinfection associated with sulfonamides?

<p>All of the above (D)</p> Signup and view all the answers

What drug interacts with sulfonamides to cause crystalluria?

<p>Methenamine</p> Signup and view all the answers

What drug is often combined with trimethoprim?

<p>Sulfamethoxazole</p> Signup and view all the answers

Trimethoprim is concentrated in the prostate and urine.

<p>True (A)</p> Signup and view all the answers

Trimethoprim can cause megaloblastic anemia.

<p>True (A)</p> Signup and view all the answers

What can reverse the effects of trimethoprim-induced folic acid deficiency?

<p>Folinic acid</p> Signup and view all the answers

Trimethoprim can cause hyperkalemia.

<p>True (A)</p> Signup and view all the answers

What medication class is contraindicated with trimethoprim due to its potassium-sparing effect?

<p>ACE inhibitors</p> Signup and view all the answers

What is the combination of trimethoprim and sulfamethoxazole called?

<p>Co-trimoxazole</p> Signup and view all the answers

Co-trimoxazole has greater antimicrobial activity than equivalent amounts of either drug used alone.

<p>True (A)</p> Signup and view all the answers

What is a common opportunistic infection that co-trimoxazole is effective against?

<p>Pneumocystis carinii pneumonia</p> Signup and view all the answers

What are some alternative urinary tract antiseptics that can be used when fluoroquinolones and co-trimoxazole are ineffective due to resistance?

<p>Methenamine, nitrofurantoin, and fosfomycin</p> Signup and view all the answers

What are the two main reasons why these alternative urinary tract antiseptics are effective?

<p>They have efficacy against common urinary tract pathogens and they achieve high concentrations in the urine.</p> Signup and view all the answers

What is the mechanism of action of methenamine?

<p>It is hydrolyzed to ammonia and formaldehyde in acidic urine.</p> Signup and view all the answers

Methenamine is contraindicated in patients with hepatic insufficiency.

<p>True (A)</p> Signup and view all the answers

What is the mechanism of action of nitrofurantoin?

<p>It inhibits DNA and RNA synthesis.</p> Signup and view all the answers

Nitrofurantoin can cause pulmonary fibrosis.

<p>True (A)</p> Signup and view all the answers

What formulation of nitrofurantoin can reduce gastrointestinal toxicity?

<p>The microcrystalline formulation</p> Signup and view all the answers

Flashcards

Fluoroquinolones

Synthetic antibacterial drugs that are derivatives of quinolone.

DNA Gyrase

An enzyme responsible for reducing torsional stress during DNA replication by breaking and re-ligating double-stranded DNA.

Topoisomerase IV

An enzyme that separates daughter chromosomes after DNA replication is complete.

Mechanism of Action of Fluoroquinolones

Fluoroquinolones bind to DNA gyrase and topoisomerase IV, preventing proper DNA replication and cell division.

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Targeted Action in Gram-Negative and Gram-Positive Bacteria

Fluoroquinolones target DNA gyrase in gram-negative bacteria and topoisomerase IV in gram-positive bacteria, effectively killing them.

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Human Cell Toxicity

The enzyme topoisomerase II, responsible for removing positive supercoils in human DNA, has a low affinity for fluoroquinolones, explaining the low toxicity to human cells.

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Helicases

Enzymes that utilize ATP to unwind double-stranded DNA molecules into single strands, necessary for DNA replication.

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Replication Fork

The region on DNA where the double helix is unzipped, creating an area for DNA polymerases to synthesize new DNA strands.

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DNA Polymerase

An enzyme that synthesizes new DNA strands using existing strands as templates during DNA replication.

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Activity Against Intracellular Organisms

Fluoroquinolones can accumulate within macrophages and leukocytes, extending their activity against intracellular bacteria, such as Listeria, Chlamydia, and Mycobacterium.

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Drug Interaction: Quinolones + Theophylline

Fluoroquinolones can interact with theophylline, potentially increasing its blood levels and side effects.

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Drug Interaction: Quinolones + Warfarin

Fluoroquinolones can interact with warfarin, potentially increasing its effect and risk of bleeding.

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Folic Acid

Essential coenzyme for synthesizing DNA, RNA, and specific amino acids. Without it, cell growth and division are impossible.

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Human Folate Metabolism

Humans utilize dietary folate to make the critical folate derivative, tetrahydrofolic acid, essential for cell growth and division.

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Bacterial Folate Metabolism

Many bacteria cannot absorb folate derivatives and rely on producing folate de novo through different pathways.

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Folate Antagonists

A class of antimicrobial drugs that inhibit the synthesis of folic acid in bacteria.

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Sulfonamides

Antibacterials that were among the first used in clinical practice but are rarely prescribed alone today due to widespread bacterial resistance, especially in developed countries.

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Mechanism of Action of Sulfonamides

Sulfonamides inhibit the synthesis of dihydrofolic acid, an essential precursor to tetrahydrofolic acid (THF), preventing bacterial growth.

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Spectrum of Activity of Sulfonamides

Sulfonamides have effectiveness against both gram-negative and gram-positive bacteria, including common organisms like Enterobacteriaceae, Haemophilus influenzae, Streptococcus spp., Staphylococcus spp., and Nocardia.

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Pharmacokinetics of Sulfonamides: Absorption

Most sulfonamides are well absorbed after oral administration, except for sulfasalazine. Topical creams containing silver sulfadiazine are used for burn treatment.

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Pharmacokinetics of Sulfonamides: Distribution

Sulfonamides bind to serum albumin and distribute widely in body tissues, including crossing the placenta and entering fetal tissues.

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Pharmacokinetics of Sulfonamides: Metabolism

Sulfonamides are metabolized in the liver, producing a byproduct that may precipitate in the kidneys and cause crystalluria.

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Crystalluria and Nephrotoxicity

A possible adverse effect of sulfonamides resulting from the precipitation of the drug in the kidneys, potentially leading to kidney damage.

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Hypersensitivity Reactions

Hypersensitivity reactions like rashes, angioedema, or Stevens-Johnson syndrome, can occur with sulfonamide use.

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Hemolytic Anemia

Sulfonamides can cause hemolytic anemia in patients with the genetic condition glucose-6-phosphate dehydrogenase (G6PD) deficiency.

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Kernicterus

Sulfonamides can cause a buildup of bilirubin in the brain of newborns, leading to a serious condition called kernicterus.

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Sulfonamides: Drug Interactions

Sulfonamides interact with CYP2C9 and can increase the plasma levels of drugs like warfarin, phenytoin, and methotrexate, potentially causing increased side effects.

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Trimethoprim

A sulfonamide drug specifically used for urinary tract infections.

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Pharmacokinetics and Adverse Effects of Trimethoprim

Trimethoprim concentrates in the prostate and urine, making it an effective treatment for prostate and urinary tract infections. However, it can also cause megaloblastic anemia and granulocytopenia.

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Co-trimoxazole

A combination of trimethoprim and sulfamethoxazole, offering greater antimicrobial activity than either drug alone.

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Indications for Co-trimoxazole

Co-trimoxazole is commonly used for gastrointestinal infections, prostate and urinary tract infections, respiratory infections, and Pneumocystis carinii pneumonia, a common opportunistic infection in AIDS patients.

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Alternative Urinary Tract Antiseptics

Agents like methenamine, nitrofurantoin, and fosfomycin are used to treat urinary tract infections, especially in cases of resistance to traditional fluoroquinolones and co-trimoxazole.

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Methenamine (hexamine, urotropine)

A urinary tract antiseptic that is hydrolyzed to ammonia and formaldehyde in acidic urine (pH ≤ 5.5), leading to bacterial cell death.

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Clinical Tips for Methenamine

Methenamine is often formulated with a weak acid, like hippuric acid, to maintain urine acidity and promote formaldehyde production.

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Nitrofurantoin

A urinary tract antiseptic that inhibits DNA and RNA synthesis. Common adverse events include nausea, vomiting, and diarrhea. Long-term use can cause pulmonary fibrosis, neuropathy, and autoimmune hepatitis.

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Study Notes

Fluoroquinolones

  • Quinolones are synthetic antibacterial drugs
  • Nalidixic acid, developed in the early 1960s, led to modifications of the quinolone nucleus, expanding the spectrum of activity, improving pharmacokinetics, and increasing resistance to common drug resistance mechanisms.
  • Quinolone antimicrobials quickly integrated into human and agricultural medicine.
  • However, overuse led to rising resistance rates in both gram-negative and gram-positive organisms.
  • Fluoroquinolones inhibit DNA gyrase (topoisomerase II) and topoisomerase IV, causing DNA replication failure and cell lysis.
  • DNA gyrase reduces torsional stress ahead of replicating DNA forks. Topoisomerase IV helps separate replicated chromosomes.
  • Fluoroquinolones bind to these enzymes, interrupting DNA ligation. This increases permanent chromosomal breaks, triggering cell lysis.
  • Gram-negative organisms are targeted by DNA gyrase inhibition. Gram-positive organisms are targeted by topoisomerase IV inhibition.
  • Mammalian cells have topoisomerase II, which has very low affinity for fluoroquinolones, decreasing toxicity to host cells.
  • Fluoroquinolones are available in various generations each showing different antimicrobial spectra and applications.
  • Fluoroquinolones have good oral bioavailability
  • Fluoroquinolones distribute well in tissues, including bone.
  • Iron, zinc, and calcium interfere with fluoroquinolone absorption.
  • Dosage adjustments are required in renal dysfunction, except for moxifloxacin.
  • Accumulation in macrophages and polymorphonuclear leukocytes results in activity against intracellular organisms like Listeria, Chlamydia, and Mycobacteria.

Adverse Effects

  • Gastrointestinal distress
  • Central nervous system (CNS) effects like rashes and photosensitivity
  • Connective tissue problems, avoid during pregnancy, breastfeeding, and in individuals under 18.
  • QT prolongation (moxifloxacin, gemifloxacin, levofloxacin)
  • High risk of causing superinfections (C. difficile, candida albicans, streptococci)

Drug Interactions

  • First-generation quinolones and theophylline
  • Second-generation quinolones and warfarin

Folic Acid Antagonists

  • Folic acid is crucial for the synthesis of RNA, DNA, and amino acids.
  • Humans obtain folic acid from their diet and convert it to tetrahydrofolic acid.
  • Many bacteria synthesize folic acid independently (de novo).

Sulfonamides

  • Sulfa drugs are among the first antibiotics.
  • Currently, they are less frequently prescribed due to drug resistance.
  • Developing countries often use them due to their low cost and efficacy.
  • Sulfonamides act by inhibiting bacterial dihydrofolate synthesis.
  • Inhibition of bacterial folic acid synthesis prevents DNA and RNA production, hindering cell growth and replication.
  • They are well absorbed after oral administration, except for sulfasalazine.
  • They are widely distributed in body tissues, including the cerebrospinal fluid. They cross the placental barrier.
  • They are primarily metabolized in the liver and become devoid of antimicrobial activity. Acetylated products retain some toxicity.

Adverse Effects of Sulfonamides

  • Crystalluria and potential kidney damage due to precipitation at specific pHs. This can be addressed by adequate hydration and alkalinization of urine.
  • Hypersensitivity reactions, including rashes, angioedema, and Stevens-Johnson syndrome.
  • Hemolytic anaemia (in patients with G6PD deficiency); granulocytopenia and thrombocytopenia; aplastic anaemia; and other blood dyscrasias.
  • Kernicterus (Bilirubin-associated brain damage in newborns) due to bilirubin displacement from serum albumin.

Drug Interactions

  • CYP2C9, plasma protein binding level of warfarin, phenytoin, and methotrexate.

Contraindications

  • Avoid sulfonamides in newborns and infants under 2 months of age as well as in pregnant women at term.

Trimethoprim

  • Trimethoprim concentrates in the prostate and urine.
  • Causes megaloblastic anaemia, granulocytopenia (folate-deficiency issues) and Hyperkalemia.
  • Folate deficiency effects are reversible with simultaneous folinic acid administration, which does not affect bacteria.
  • Avoid in cases of ACEI use due to hyperkalemia risk

Co-trimoxazole

  • Trimethoprim and sulfamethoxazole combination with potent antimicrobial activity.
  • Used in gastrointestinal infections (shigellosis, non-typhoid salmonella), urinary tract infections (including prostate and vaginal infections), and respiratory infections (influenzae), including Pneumocystis carinii pneumonia (opportunistic infection related to AIDS).

Urinary Tract Antiseptics

  • Fluoroquinolones and cotrimoxazole were initial choices for urinary tract infections.
  • Resistance has increased. Methenamine, nitrofurantoin, and fosfomycin are alternative agents.
  • These alternatives are often used due to their efficacy against common pathogens and high concentrations in urine.

Methenamine

  • Methenamine (hexamine/urotropine) is hydrolysed to ammonia and formaldehyde in acidic urine (pH ≤ 5.5).
  • Formaldehyde denatures microbial proteins and nucleic acids, leading to bacterial cell death.
  • Use is restricted in hepatic insufficiency.

Nitrofurantoin

  • Inhibits DNA and RNA synthesis.
  • Effective against E. coli, Klebsiella spp., Enterococcus spp., and Staphylococcus spp.
  • Common side effects include nausea, vomiting, and diarrhea.
  • Microcrystalline formulation reduces gastrointestinal toxicity.
  • Prolonged exposure can cause pulmonary fibrosis, neuropathy, and autoimmune hepatitis. Especially, in patients with impaired renal function.

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Fluoroquinolones PDF

Description

Explore the world of fluoroquinolones, synthetic antibacterial drugs that have revolutionized medicine since the 1960s. Learn how these drugs work by inhibiting key enzymes involved in DNA replication, and understand the implications of their overuse in medicine and agriculture. This quiz covers the mechanisms, applications, and resistance issues associated with fluoroquinolones.

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