International review of drugs in acute porphyria—1980

Abstract

In the years following the very successful review of the effects of drugs in acute intermittent porphyria by Wetterberg (1976), many new items of information have accrued on this subject. The aim of this current review (initiated at the International Meeting on Porphyrins and the Porphyrias in Buenos Aires, 1979) is to up-date this information with especial reference to the potential clinical effects of drugs. It will contain no information on the effects of drugs in the non-acute porphyrias, since in these diseases only circumscribed groups of drugs may be linked with exacerbation of the disease, such as exacerbation of cutaneous hepatic porphyria (porphyria cutanea tarda) by ethanol and chlorinated hydrocarbons or a similar exacerbation of erythropoietic protoporphyria by ethanol (MathewsRoth, 1980). The importance of this review may be understood in the description of the acute porphyrias as a group of pharmacogenetic diseases, that is a group of genetically defined diseases which show an idiosyncratic reaction to many common drugs. The porphyrias may thus be induced into attack in the presence of certain drugs especially drugs known to be inducers of cytochrome P-450 mediated oxidation although other mechanisms are undoubtedly present (Maxwell & Meyer, 1976; Meyer, 1978). Because of the multiplicity of drug structures, it is usually very difficult to predict whether or not a drug may induce excess porphyrin synthesis although it has reasonably been suggested that all lipophilic drugs must be suspect in this respect (De Matteis, 1971; Smith & De Matteis, 1980; Sweeney, 1980). Certain chemical groups have been linked with induction of porphyria, such as ally1 groups (Goldberg & Rimington, 1954), the basic nucleus of the barbiturates (De Matteis, 1967) and certain steroids (Paxton et al., 1976). Typically, drugs such as the barbiturates and diphenylhydantoin act by early depletion of free haem and thus induce delta-aminolaevulinic acid synthase. Although depletion of free haem is probably the principal mechanism in action, it has been noted that the porphyrinogenic barbiturates may decrease the activity of steroid 5-a-reductase (Kappas et al., 1977), thus mimicking the ratio difference of 5-p to S-a steroids found in acute porphyrias (Moore er al., 1973). In recent years, a number of very useful reviews of porphyrinogenic effects of specific categories of drugs have been produced, especially drugs which might potentially be used during an acute porphyric attack, such as anti-hypertensive drugs (Anderson, 1978), anaesthetic drugs (Parikh & Moore, 1978) and anticonvulsant drugs (McCall, 1980; Larson et al.. 1978). For further information on these drugs and the methods used to arrive at the classification, the reader should consult the appropriate papers. There are three means by which drugs may be implicated in induction of attacks of porphyria. Firstly, there is analysis of the effects of the drugs in various types of cell culture on either production of porphyrins, or induction of ALA synthase activity. This is a very sensitive means of assessment and will often produce false positive results. Secondly, there is a similar assessment in the effects of drugs either on their own or in combination with proven porphyrinogens in whole animals. This suffers from the physiological differences in drug metabolism routes between rats and man and thus in differences in drug sensitivity between these two species. Lastly, there is the anecdotal evidence of porphyrinogenicity in man. either through induction of acute attacks by drugs or by measurement of ALA synthase activity or porphyrins in human tissues and excreta. This information may be culled from the literature and from the personal experience of workers in the field. This current review has concentrated upon this last approach. Information has been requested of a large number of investigators in the world who have experience of the porphyrias and their treatment. From the volumes of evidence that they have submitted and from lists of drugs considered by them to be safe and unsafe for use in the porphyrias, the following tables have been generated. In many cases, the information depends not only on the third approach, but also on the first and second forms of approach. For this reason, it is likely that all drugs listed as “safe” for use in the porphyrias are safe, but that drugs listed as “unsafe” in the porphyrias are not definitively so and that in many cases, porphyric patients may have been treated with one or more of these drugs with no ill effect. Equally, one can say that none of the drugs listed as unsafe for use in the porphyrias should be used in these diseases without extreme care, lest one potentiate an acute attack of porphyria.