The drug hydralazine is a vasodilator used for the treatment of hypertension. In a significant proportion of individuals it causes a serious adverse effect, drug-induced lupus erythematosus (LE). This toxic effect, believed to have an immunological basis, involves a number of interesting features. Thus, there are a number of predisposing factors which make it possible to identify patients at risk, although the mechanism(s) underlying some of these predisposing factors are unknown. When the occurrence in the exposed population is examined in the light of some of these factors the incidence can be seen to be extremely high. The predisposing factors identified to date are:
2 duration of therapy
4 HLA type
Thus, if the exposed population is divided into males and females and by the various doses administered, the incidence in susceptible populations can be appreciated (table 7.7).
Thus, the highest incidence recorded in one study was over 19% in the most susceptible population— females taking 100 mg of hydralazine twice daily. We examine each of these factors in turn.
There is an increase in the incidence of hydralazine-induced LE in the exposed population with increasing dose as can be seen in table 7.7. However, patients who develop LE do not have a significantly different cumulative intake of hydralazine from those patients who do not develop the syndrome. This latter observation is consistent with the absence
Duration of therapy
The adverse effect develops slowly, typically over many months and there is a mean development time of around 18 months.
The LE syndrome only develops in those patients with the slow acetylator phenotype. Metabolic studies have shown that the metabolism of hydralazine involves an acetylation step (figure 7.54) which is influenced by the acetylator phenotype.
The tissue type seems to be a factor as there is a preponderance of the HLA-type DR4 in patients who develop the syndrome. Thus, in one study an incidence of 73% for this HLA type was observed in patients suffering the LE syndrome compared with an incidence of 33% in controls and 25% in patients not developing the LE syndrome.
Females seem to be more susceptible to hydralazine-induced LE than males. The ratio may be as high as 4:1.
Hydralazine-induced LE causes inflammation in various organs and tissues giving rise to a number of different symptoms. Thus patients suffer from arthralgia and myalgia, skin rashes and sometimes vasculitis. There may also be hepatomegaly, splenomegaly, anaemia and leucopenia. Two particular characteristics detectable in the blood are antinuclear anti-bodies and LE cells. Antinuclear antibodies (ANA) are directed against single-stranded DNA and de-oxyribonucleoprotein such as histones and occur in at least 27% of patients taking the drug, but not all of these develop the LE syndrome. Indeed, in one study over 3 years, 50% of patients had an ANA titre of 1:20 or more. Antibodies directed against other cellular and tissue constituents such as DNA and immunoglobulins are also present, and antibodies against synthetic hydralazine-protein conjugates have also been detected. There are thus various autoantibodies present and if the auto-antigens are released by cellular breakdown, a type III immune reaction
can occur where an immune complex is formed which is deposited in small blood vessels and joints, giving rise to many of the symptoms. The immunoglobulins IgG and IgE act as both auto-antibody and antigen and hence immune complexes form. Such complexes stimulate the complement system leading to inflammation, infiltration by polymorphs and macrophages and the release of lysosomal enzymes. LE cells are neutrophil polymorphs which have phagocytosed the basophilic nuclear material of leucocytes which has been altered by interaction with antinuclear antibodies. The development of ANA requires a lower intake of hydralazine and occurs more quickly in slow acetylators than in rapid acetylators, and rapid acetylators have significantly lower titres of ANA than slow acetylators. There is also a significant correlation between the cumulative dose of hydralazine and the development of ANA, but as indicated above patients who develop LE do not have a significantly different cumulative intake of hydralazine from those patients who do not develop the syndrome.
The mechanism of hydralazine-induced LE is not currently understood but the evidence available indicates that it has an immunological basis. Hydralazine is a chemically reactive molecule and it is also metabolized to reactive metabolites, possibly free radicals, by the cytochromes P-450 system (figure
7.55), which bind covalently to protein. The production of the metabolite phthalazinone correlates with the binding in vitro. However,
no antibodies against such conjugates with human microsomal protein were detected in the sera of patients with the LE syndrome. Hydralazine may also be a substrate for the benzylamine oxidase system found in vascular tissue, and for a peroxidase-mediated metabolic activation system which occurs in cells such as activated leucocytes. Thus a myeloperxidase/H2O2/Cl- system will metabolize hydralazine to phthalazinone and phthalazine, and this may also involve the production of reactive intermediates. This system has also been suggested to be involved in the activation of the drug procainamide which similarly causes a LE syndrome. Metabolic studies have shown that slow acetylators excrete more unchanged hydralazine and metabolize more via oxidative pathways (figure 7.54). Patients with the LE syndrome excrete more phthalazinone than control patients although this is not statistically significant. There is no difference between males and females in the nature or quantities of urinary metabolites of hydralazine detected however and so metabolic differences do not currently explain the sex difference in susceptibility. However, there is clearly scope for the formation of protein-drug conjugates which may be antigenic and hydralazine also reacts with DNA. Synthetic hydralazine-protein conjugates will stimulate the production of antibodies in rabbits and antibodies in human sera from patients with the LE syndrome will recognize and agglutinate rabbit red blood cells to which hydralazine has been chemically attached. Hydralazine will abolish this reaction in vitro indicating that it is the hapten or is similar to it.
Thus interaction of hydralazine or a metabolite with macromolecules may underlie the immune response. An alternative or additional hypothesis involves inhibition of the complement system. The complement system helps remove immune complexes by solubilization, but if it is inhibited deposition and accumulation of such complexes would be increased. Hydralazine and some of its metabolites interfere with part of the complement system, inhibiting the covalent binding of complement C4 by reaction with the thioester of activated C4. However, the conentrations required are high relative to the normal therapeutic concentration. More recently it has been shown that hydralazine inhibits DNA methylation in the T-cell. The inhibition of DNA methyl transferase may initiate immune reactions via activation of genes as a result of this interference with DNA methylation. However, although the mechanism of hydralazine-induced LE is not yet understood, it is an important example of drug-induced toxicity for two reasons:
a It illustrates the role and possibly the requirement for various predisposing factors in the development of an adverse drug reaction in a human population. An understanding of this should allow reduction of such adverse drug reactions by improved surveillance and prescribing. b It reveals the difficulties of testing for this type of reaction in experimental animals when the various predisposing factors may not be present. However, the LE syndrome does occur in certain strains of mice and acetylation rates do vary between strains of laboratory animals. Using such specific models might therefore allow improved prediction.
7.12 Multi-organ toxicity
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