PubMed · 8333213
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D Soyka. 1993-06-12. [Tension headache].. https://pubmed.ncbi.nlm.nih.gov/8333213/
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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 maintain intact heme synthesis and regulation, to study the effects of antihypertensives and analgesics on porphyrin accumulation. Cells were treated with 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 microM), along with desferrioxamine. Porphyrins were measured spectrofluorometrically, as uro-, copro,- and protoporphyrin. The evaluated drugs included six antihypertensives (two calcium channel blockers, an angiotensin receptor antagonist, and three inhibitors of angiotensin converting enzyme) and eight analgesics. Of the calcium channel blockers tested, nifedipine greatly increased porphyrin accumulation, whereas diltiazem caused only a slight increase. Losartan (an angiotensin receptor antagonist), captopril, or lisinopril (two angiotensin converting enzyme inhibitors) produced only small increases in porphyrin accumulation. In contrast, enalapril (another angiotensin converting enzyme inhibitor) substantially increased porphyrin accumulation when given in high concentrations. Among the analgesics tested, fentanyl and tramadol produced the highest porphyrin 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 with acute porphyrias may be at greater risk for developing porphyric attacks when treated with nifedipine (compared with diltiazem), enalapril (compared with captopril or lisinopril), and tramadol (compared with the other analgesics).
Antinociceptive synergism between spinally administered morphine and clonidine decreases to an additive interaction in morphine- and clonidine-tolerant mice. Spinally administered protein kinase C (PKC) inhibitors also decrease the synergism to addition. To determine whether chronic morphine or clonidine treatment alters spinal PKC activity, the present studies measured PKC activity and expression of PKC isoform proteins in spinal cord cytosol and membrane fractions. Mice were treated for 4 days with either placebo pellets, morphine pellets, s.c. saline, or s.c. clonidine. Morphine pellet-implanted mice were tolerant to morphine-induced tail flick antinociception, but not cross-tolerant to clonidine. Clonidine-pretreated mice were tolerant to clonidine, but not cross-tolerant to morphine. Induction of morphine tolerance produced a 2-fold lower Km value for PKC (8.24 +/- 1.67 microM in placebo pellet vs 4.43 +/- 1.24 microM in morphine pellet) in cytosol, but not membrane fractions from spinal cord. Vmax values were not different. No difference in Km or Vmax values was found between proteins from saline- and clonidine-pretreated animals. Immunoreactive cPKCalpha, betaI, and gamma isoforms decreased 14, 26, and 17%, respectively, in cytosol from morphine-tolerant animals. No difference in PKC isoforms was found in the membranes or in fractions from clonidine-tolerant mice. Morphine tolerance, but not clonidine tolerance, enhanced PKC activity while decreasing protein expression.
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