Effects of selected antihypertensives and analgesics on hepatic porphyrin accumulation - Implications for clinical porphyria

When patients with acute porphyrias are treated with antihypertensives and analgesics, they could be placed at increased risk of developing porphyric attacks, since little is known about the potential for many of these drugs to induce these attacks. We used primary chick embryo liver cells, which ma intain intact heme synthesis and regulation, to study the effects of antihy pertensives and analgesics on porphyrin accumulation. Cells were treated wi th desferrioxamine to block heme synthesis partially, simulating conditions encountered in porphyric patients. Typically, cells were treated for 20 hr with the test drugs (3.16 to 1000 mu M), along with desferrioxamine. Porph yrins were measured spectrofluorometrically, as uro-, copro,- and protoporp hyrin. The evaluated drugs included six antihypertensives (two calcium chan nel blockers, an angiotensin receptor antagonist, and three inhibitors of a ngiotensin converting enzyme) and eight analgesics. Of the calcium channel blockers tested, nifedipine greatly increased porphyrin accumulation, where as diltiazem caused only a slight increase. Losartan (an angiotensin recept or antagonist), captopril, or lisinopril (two angiotensin converting enzyme inhibitors) produced only small increases in porphyrin accumulation. In co ntrast, enalapril (another angiotensin converting enzyme inhibitor) substan tially increased porphyrin accumulation when given in high concentrations. Among the analgesics tested, fentanyl and tramadol produced the highest por phyrin accumulations. Nalbuphine, hydrocodone, oxycodone, and dezocine were moderately or weakly porphyrogenic, whereas buprenorphine and morphine did not increase porphyrin accumulation. These studies suggest that patients w ith acute porphyrias may be at greater risk for developing porphyric attack s when treated with nifedipine (compared with diltiazem), enalapril (compar ed with captopril or lisinopril), and tramadol (compared with the other ana lgesics). (C) 1999 Elsevier Science Inc.