Triggers
Acute porphyria can be triggered by a number of drugs, most of which are believed to trigger it by interacting with enzymes in the liver which are made with heme. Such drugs include:
Sulfonamides, including sulfadiazine, sulfasalazine and trimethoprim/sulfamethoxazole. Sulfonylureas like glibenclamide, gliclazide and glimepiride, although glipizide is thought to be safe. Barbiturates including thiopental, phenobarbital, primidone, etc. Systemic treatment with antifungals including fluconazole, griseofulvin, ketoconazole and voriconazole. (Topical use of these agents is thought to be safe due to minimal systemic absorption.) Certain antibiotics like rifapentine, rifampicin, rifabutine, isoniazid, nitrofurantoin and, possibly, metronidazole. Ergot derivatives including dihydroergotamine, ergometrine, ergotamine, methysergide, etc. Certain antiretroviral medications (e.g. indinavir, nevirapine, ritonavir, saquinavir, etc.) Progestogens
Some anticonvulsants including: carbamazepine, ethosuximide, phenytoin, topiramate, valproate. Some painkillers like dextropropoxyphene, ketorolac, metamizole, pentazocine
Some cancer treatments like bexarotene, busulfan, chlorambucil, estramustine, etoposide, flutamide, idarubicin, ifosfamide, irinotecan, ixabepilone, letrozole, lomustine, megestrol, mitomycin, mitoxantrone, paclitaxel, procarbazine, tamoxifen, topotecan
Some antidepressants like imipramine, phenelzine, trazodone
Some antipsychotics like risperidone, ziprasidone
Some retinoids used for skin conditions like acitretin and isotretinoin
Miscellaneous others including: cocaine, methyldopa, fenfluramine, disulfiram, orphenadrine, pentoxifylline, and sodium aurothiomalate. Pathogenesis
In humans, porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, catalase, peroxidase, and P450 liver cytochromes.The body requires porphyrins to produce heme, which is used to carry oxygen in the blood among other things, but in the porphyrias there is a deficiency (inherited or acquired) of the enzymes that transform the various porphyrins into others, leading to abnormally high levels of one or more of these substances.
In 2005, it was suggested that arsenic (which is known to be porphyrogenic) given to George III with antimony may have caused his porphyria. This study found high levels of arsenic in King Georges hair. In 2010, one analysis of historical records argued that the porphyria claim was based on spurious and selective interpretation of contemporary medical and historical sources. The mental illness of George III is the basis of the plot in The Madness of King George, a 1994 British film based upon the 1991 Alan Bennett play, The Madness of George III. The closing credits of the film include the comment that the Kings symptoms suggest that he had porphyria and notes that the disease is "periodic, unpredictable, and hereditary". The traditional argument that George III did NOT have porphyria, but rather bipolar disorder, is thoroughly defended by Andrew Roberts in his new biography, "The Last King of America." Descendants of George III. Among other descendants of George III theorized by the authors of Purple Secret to have had porphyria (based on analysis of their extensive and detailed medical correspondence) were his great-great-granddaughter Princess Charlotte of Prussia (Emperor William IIs eldest sister) and her daughter Princess Feodora of Saxe-Meiningen. They uncovered better evidence that George IIIs great-great-great-grandson Prince William of Gloucester was reliably diagnosed with variegate porphyria. Mary, Queen of Scots. It is believed that Mary, Queen of Scots, King George IIIs ancestor, also had acute intermittent porphyria, although this is subject to much debate.