5. Quinolones, Folic Acid Antagonists and Urinary Antiseptics

Question 1

Types of fluoroquinolones

Answer 1

1. Ciprofloxacin
2. Levofloxacin
3. Moxifloxacin

Question 2

MOA of fluoroquinolones

Answer 2

Targets DNA gyrase, primarily in gram - bacteria and topoisomerase IV in gram + to inhibit DNA replication

• DNA gyrase → introduces negative supercoils into the DNA to prevent excessive positive supercoiling
• Topoisomerase IV → promotes separation of chromosomal DNA into daughter cells

Eukaryotic cells do not contain DNA gyrase. They contain a mechanistically similar DNA topoisomerase II, which can be inhibited by quinolones at higher conc.

Question 3

Pharmacokinetics of fluoroquinolones

Answer 3

Ingestion of fluoroquinolones with calcium or other divalent cations such as aluminium - or magnesium containing antacids, or dietary supplements containing iron or zinc can reduce the absorption
→ 2 hours apart
→ best on empty stomach

Question 4

Adverse effects of fluoroquinolones

Answer 4

1. Nausea, vomiting and diarrhoea
2. Increase risk of C. diff colitis as they clear the bowel flora, especially ciprofloxacin
3. Headache and dizziness or lightheadness may occur → patients with CNS disorders such as epilepsy should be treated cautiously
4. Phototoxicity
5. Increased risk of tendinitis or tendon rupture
6. Not recommended for infants or children < 18 years of age → joint problems (arthropathy)
7. May prolong the QTc interval
8. Peripheral neuropathy

Question 5

Contraindications in fluoroquinolone

Answer 5

1. Myasthenia gravis due to exacerbation of muscle weakness

2. Pregnancy (cat C) and breastfeeding

Question 6

Drug interactions with fluoroquinolones

Answer 6

1. Increase serum levels of theophylline by inhibiting its metabolism
2. Increase serum levels of warfarin and cyclosporin

Question 7

Types of folate synthesis inhibitors

Answer 7

1. Sulfonamides
2. Trimethoprim
3. Cotrimoxazole

Question 8

MOA of sulfonamides

Answer 8

Competitive inhibitors of dihydropteroate synthase (the bacterial enzyme responsible for the incorporation of para-aminobenzoic acid (PABA) into dihydropteroic acid, the immediate precursor of folic acid)
→ bacteriostatic against microorganisms that synthesize their own folic acid

Question 9

Adverse effects of sulfonamides

Answer 9

1. Crystalluria → nephrotoxicity
2. Hypersensitivity → rashes, angioedema, Stevens-Johnson syndrome
3. Hematopoietic disturbances → Hemolytic anemia in G6PD deficiency, thrombocytopenia
4. Kernicterus

Question 10

Drug potentiation with sulfonamides

Answer 10

Transient potentiation of the anticoagulant effect of warfarin results in the displacement from binding sites on serum albumin have been reported in patients receiving both sulfamethoxazole and warfarin → increased monitoring

Question 11

Contraindications in sulfonamides

Answer 11

Danger of kernicterus → avoid in newborns and infants less than 2 months of age, as well as pregnant women at term

Question 12

MOA of trimethoprim

Answer 12

Inhibits the reduction of dihydrofolic acid by dihydrofolate reductase to its active form → decrease availability of tetrahydrofolate cofactors required for purine, pyrimidine, and amino acid synthesis

Question 13

Resistance to trimethoprim

Answer 13

1. Resistance in gram - bacteria is due to the presence of an altered dihydrofolate reductase that has lower affinity for trimethoprim
2. Efflux pumps and decreased permeability to the drug may play a role

Question 14

Adverse effects of trimethoprim

Answer 14

Folic acid deficiency → megaloblastic anemia, leukopenia, granulocytopenia, especially in pregnant patients and those having very poor diets

Effects can be reversed with simultaneous administration of folinic acid, not dihydrofolic acid

Question 15

MOA of cotrimoxazole (trimethoprim + sulfamethoxazole)

Answer 15

Synergistic antimicrobial activity of cotrimoxazole → inhibition of 2 sequential steps in the synthesis of tetrahydrofolic acid

Sulfamethoxazole → inhibits the incorporation of PABA into dihydrofolic acid precursors
Trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate

Question 16

Adverse effects of cotrimoxazole

Answer 16

1. Skin reactions → rash
2. Photosensitivity
3. GI effects → nausea and vomiting
4. Glossitis and stomatitis
5. Hemolytic anemia may occur with G6PD deficiency due to sulfamethoxazole component
6. Megaloblastic anemia, leukopenia, thrombocytopenia → reversed by concurrent administration of folinic acid
7. Caution in pregnancy as it can cause folate deficiency

Question 17

Drug interactions with cotrimoxazole

Answer 17

Can increase the half life of phenytoin, enhance the effect of warfarin

Question 18

Example of urinary antiseptic

Answer 18

Nitrofurantoin

Question 19

MOA of nitrofurantoin

Answer 19

Nitrofurantoin bacteria reduce the drug to a highly active intermediate that inhibits various enzymes and disrupts the synthesis of proteins, DNA, RNA and metabolic processes

Question 20

Adverse effects of nitrofurantoin

Answer 20

1. Nausea, vomiting and diarrhoea
2. Various hypersensitivity reactions occasionally occur including chills and fever
3. Leukopenia, hemolytic anemia (associated with G6PD deficiency)
4. Cholestatic jaundice, and hepatocellular damange (rare)
5. Elderly patients are especially susceptible to the pulmonary toxicity of nitrofurantoin
6. Peripheral neuropathies (in patients with impaired renal functions & long-continued treatment) (rare)
7. Prolonged incubation period to onset of liver injury → mistaken or delayed diagnosis

Question 21

Contraindications in nitrofurantoin

Answer 21

1. Impaired renal function
2. Pregnant women, during labour and delivery, or when the start of labour is imminent
3. Infants < 1 month of age