Quinolones selective toxicity

As described in section 4.1, the DNA double helix must unwind to allow access ofthe polymerase enzymes to produce two new strands ofDNA. This is facilitated by DNA gyrase, the target of the quinolones. Some agents interfere with the unwinding of the chromosome by physical obstruction. These include the acridine dyes, of which the topical antiseptic proflavine is the most familiar, and the antimalarial acridine, mepacrine. They prevent strand separation by insertion (intercalation) between base pairs from each strand, but exhibit very poor selective toxicity. 

Nalidixic acid and all its analogs act by selectively inhibiting bacterial DNA synthesis. The actual biochemical target of the quinolones is the enzyme DNA-gyrase, a topoisomerase enzyme found only in procaryotic cells. This accounts for the selective toxicity of these drugs. 

In contrast, decreases in theophylline metabolism by selective inhibitors of CYP1A2, such as fluvoxamine and some quinolone antibiotics, or by selective and potent inhibitors of CYP3A4, such as the macrolide antibiotics, have resulted in serious theophylline toxicity (22). It is postulated that taken over time, the macrolide antibiotics act as mechanism-based inhibitors of CYP isoforms other than just CYP3A4. Some nonselective inhibitors of P450s, such as cimetidine, some p-blockers and calcium channel blockers, and others (19,22), also appear to inhibit the metabolism of theophylline enough to cause toxicity. 

Antidepressants selective serotonin reuptake inhibitors, tricyclic antidepressants Antihypertensives felodipine Antibiotics quinolones, isoniazid Bronchodilators albuterol, theophylline Corticosteroids prednisone Dopa agonists levodopa Herbals ma huang, ginseng, ephedra Nonsteroidal anti-inflammatory drugs ibuprofen Stimulants amphetamines, methylphenidate, caffeine, cocaine Sympathomimetics pseudoephedrine Thyroid hormones levothyroxine Toxicity anticholinergics, antihistamines, digoxin Withdrawal alcohol, sedatives... 

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