Hydralazine incidence

Another chemical class of drugs associated with inducing a lupus is the hydrazines. As with aromatic amines, there are few examples because most hydrazines are toxic. Hydralazine is second only to procainamide with respect to the incidence of lupus associated with its use [14], Although its present use is infrequent, the finding that it is... 

Autoantibodies to red blood cells and autoimmune hemolytic anemia have been observed in patients treated with numerous drugs, including procainamide, chlor-propaminde, captopril, cefalexin, penicillin, and methyldopa (Logue et al., 1970 Kleinman et al., 1984). Hydralazine- and procainamide-induced autoantibodies may also result in SLE. Approximately 20% of patients administered methyldopa for several weeks for the treatment of essential hypertension developed a dose-related titer and incidence of autoantibodies to erythrocytes, 1% of which presented with hemolytic anemia. Methlydopa does not appear to act as a hapten but appears to act by modifying erythrocyte surface antigens. IgG autoantibodies then develop against the modified erythrocytes. 

Table 7.9 Incidence of Hydralazine-Induced Systemic Lupus Erythematosus...

Thus, the highest incidence recorded in one study was over 19% in the most susceptible population—females taking 100 mg of hydralazine twice daily. 

There is an increase in the incidence of hydralazine-induced lupus erythematosus (LE) in the exposed population with increasing dose as can be seen in Table 7.9. 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 of a clear dose-response relationship in many cases of toxicity with an immunological basis. 

ACC/AHA guidelines (II), the combined use of hydralazine-isosorbide dinitrate may be considered as a therapeutic option in patients with reduced LV dysfunction already taking ACE inhibitors and (3 blockers and with persistent symptoms. Despite the lack of data about this vasodilator combination in patients who are intolerant of ACE inhibitors, the combined use of hydralazine and isosorbide dinitrate may be considered as an additive therapeutic option in such patients, However, compliance with this combination has generally been poor because of the large number of tablets required and the high incidence of adverse reactions. 

Commonly used drugs (other than isoniazid) affected by NAT2 polymorphism were procainamide, hydralazine, dapsone, and sulfonamides with an increase of side effects in all cases. A selective substrate of NATl is -aminosalicylic acid (PAS), but its genetic variation was never clinically important (52). Because of such lack of importance, more attention is often paid to the fact that various industrial chemicals with carcinogenic potential, and mutagenic heterocyclic amines, are substrates of both N-acetyltransferases (53). The presence or absence of these transferases will determine some incidences of cancer (54). Attempts have been made to ascribe cancer incidences in different populations to acetyltransferase differences (55). 

Slow acetylator Isoniazid Hydralazine, procainamide Phenelzine, sulfasalazine Increased incidence of peripheral neuropathy SLE-like syndrome and more prone to phenytoin toxicity Increased incidence of SLE-like syndrome More prone to side effects... 

Genetic polymorphisms of xenobiotic-metabolizing enzymes may result in expression of inactive enzymes or enzymes with a reduced or increased metabolic activity (Daly, 1995). For example, the incidence of hydralazine- and procainamide-induced lupus is higher or the disease starts earlier in individuals with the slow acetylator phenotype caused by mutant NAT-2 alleles than in individuals exhibiting the fast-acetylator phenotype (Woosley et al., 1978 von Schmiedeberg et al., 1999). 

TABLE 7.7 Incidence of hydralazine-induced systemic lupus erythematosus... 

Other adverse effects are caused by immunological reactions, of which the drug-induced lupus syndrome is the most common. Hydralazine also can result in an illness that resembles serum sickness, hemolytic anemia, vasculitis, and rapidly progressive glomerulonephritis the mechanism of these autoimmune reactions is unknown. The drug-induced lupus syndrome usually occurs after at least 6 months of continuous treatment with hydralazine, and its incidence is related to dose, sex,... 

Immunologic The incidence of lupus-like syndrome associated with hydralazine is 5-8% per year [106 ]. The proposed mechanisms are related to drug metabolites acting as haptens for T cell responses. 

In a matched case-control study using UK general practice electronic records exposure to hydralazine was associated with a substantially increased risk of lupus-like syndrome compared with deliberately selected comparator drugs [108. However, drugs did not seem to be a major cause of lupus-like syndrome, accounting for only 12% of incident cases. 

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