ANTIFOLATE DRUGS

Classification and Pharmacokinetics:
- Sulfonamides are structurally similar to p-aminobenzoic acid (PABA).
- Classification based on half-life:
  - Short-acting: Sulfacytine, Sulfisoxazole
  - Intermediate-acting: Sulfamethoxazole
  - Long-acting: Sulfadoxine
- Widely distributed in tissues and body fluids; mainly excreted in urine.

Sulfonamides target organisms that cannot utilize exogenous folate and must synthesize it from PABA, crucial for purines and nucleic acid synthesis.
They act as synthetic analogues of PABA, competitively inhibiting dihydropteroate synthase and thus inhibiting the synthesis of bacterial dihydrofolic acid.

Resistance can result from mutations leading to:
- Overproduction of PABA.
- Decreased sensitivity of dihydropteroate synthase to sulfonamides.
- Impaired permeability to sulfonamides.

Urinary tract infections (e.g., Sulfisoxazole/oral).
Acute toxoplasmosis (e.g., Sulfadiazine/oral combined with pyrimethamine).
Ulcerative colitis, enteritis, and other inflammatory bowel diseases (e.g., Sulfasalazine/oral).
Infection of burn wounds (e.g., Silver sulfadiazine/topical).
Bacterial conjunctivitis (e.g., Sulfacetamide/topical).

Hypersensitivity: Allergic reactions, fever, rashes, or rare cases of Stevens-Johnson syndrome.
Crystalluria: May precipitate in urine at acidic pH.
Hematotoxicity: Can lead to aplastic anemia, granulocytopenia, and thrombocytopenia.
Drug Interactions: Compete with warfarin and methotrexate for plasma protein binding.
Contraindications: Should be avoided in neonates and pregnant women due to the risk of kernicterus.

Mechanism of Action:
- Selectively inhibits bacterial dihydrofolic acid reductase, converting dihydrofolic acid to tetrahydrofolic acid, essential for purine and DNA synthesis.
Pharmacokinetics:
- Well absorbed from the gut and widely distributed in body fluids and tissues, including cerebrospinal fluid.

Resistance mechanisms include:
- Altered dihydrofolic acid reductase with lower affinity for Trimethoprim.
- Efflux pumps.
- Decreased permeability to the drug.

Clinical Uses:
- Oral Trimethoprim for acute urinary tract infections.
- Oral TMP-SMZ for urinary tract infections, ear infections, and respiratory tract pathogens.
- Intravenous TMP-SMZ for moderately severe to severe pneumocystis pneumonia, gram-negative bacterial sepsis, typhoid fever, shigellosis, and other urinary tract infections when oral administration is not possible.

Trimethoprim can cause megaloblastic anemia, leukopenia, and granulocytopenia.
Combination of TMP-SMZ may lead to adverse effects associated with sulfonamides.
Patients with AIDS and pneumocystis pneumonia have a higher frequency of untoward reactions to TMP-SMZ.

Introduction:
- Quinolones are a family of synthetic bactericidal drugs characterized by concentration-dependent killing.
- The first generation began with Nalidixic acid (1962), with newer drugs offering greater potency and broader antimicrobial spectrum.

Fluoroquinolones can be classified into generations based on their antimicrobial activities:
- First Generation: Nalidixic acid.
- Second Generation: Ciprofloxacin.
- Third Generation: Levofloxacin.
- Fourth Generation: Moxifloxacin.

First Generation: Uncomplicated urinary tract infections (UTIs) targeting gram-negative organisms.
Second Generation: Uncomplicated and complicated UTIs, pyelonephritis, sexually transmitted diseases, prostatitis, and skin/soft tissue infections.
Third Generation: Acute exacerbation of chronic bronchitis, community-acquired pneumonia.
Fourth Generation: Broad coverage including intra-abdominal infections, nosocomial pneumonia, and pelvic infections.

Inhibit bacterial DNA synthesis by targeting topoisomerase II (DNA gyrase) and topoisomerase IV, preventing relaxation of supercoiled DNA and interfering with separation of replicated chromosomal DNA during cell division.

Fluoroquinolones are well absorbed (bioavailability of 80-95%) and widely distributed in body fluids; oral absorption is impaired by antacids.

Effective in infections of soft tissues, bones, joints, intra-abdominal, and respiratory tract infections.
Levofloxacin and moxifloxacin are effective against most organisms associated with community-acquired pneumonia.
Used in meningococcal carrier states, tuberculosis treatment, and prophylactic management of neutropenic patients.

Resistance has rapidly emerged, particularly among staphylococci and Pseudomonas aeruginosa, due to altered targets, efflux pumps, and changes in porin structure.

Generally well tolerated; common effects include nausea, vomiting, and diarrhea.
May damage growing cartilage and cause arthropathy; not recommended for children.
Some fluoroquinolones can prolong QTc interval; monitoring is necessary in patients with known QTc prolongation.
In the elderly, may cause tendonitis and predispose to tendon rupture; should be avoided during pregnancy unless safety is documented.

Antifolate Drugs: Mechanisms, Uses, and Resistance