Idiosyncratic aplastic anemia

Mostly chloramphenicol is well tolerated with only mild gastrointestinal disturbances. However this antibiotic inhibits mitochondrial protein synthesis in red blood cell precursors in the bone marrow and thus may cause dose-dependent anemia. This dose dependent reaction should not be confused with the idiosyncratic aplastic anemia which is dose-independent and usually fatal. The onset of this idiosyncrasy which has an incidence of about 1 20 000-1 50 000 may be during the treatment or weeks to months after therapy. 

The most publicized adverse affects are those involving the hematopoietic system they are manifested by toxic bone marrow depression or idiosyncratic aplastic anemia. The bone marrow depression is dose related and is seen most frequently when daily doses exceed 4 g and plasma concentrations exceed 25 jig/mL. The bone marrow depression is characterized by anemia, sometimes with leukopenia or thrombocytopenia, but it is reversible on discontinuation of chloramphenicol. 

Chloramphenicol Prevents bacterial protein synthesis by binding to the 50S ribosomal subunit Bacteriostatic activity against susceptible bacteria Use is rare in the developed world because of serious toxicities Oral, IV hepatic clearance (half-life 2.5 h) dosage is 50-100 mg/kg/d in four divided doses Toxicity Dose-related anemia, idiosyncratic aplastic anemia, gray baby syndrome... 

Idiosyncratic aplastic anemia occurs only in humans exposed to chloramphenicol. The reaction is rare (1 in 30000) and not dose related. The toxic effects are related to the presence of the para-nitro group on the chloramphenicol molecule. Florfenicol lacks this group and is not associated with aplastic anemia in any species. Long-term chloramphenicol therapy (>14 days) is associated with dose-related anemia and pancytopenia through a decrease in protein synthesis in the bone marrow, especially in cats. Florfenicol may cause similar reversible suppression of the myeloid series in bone marrow, but this does not appear to be clinically significant during shortterm treatment regimens. 

Marsh JC, Chowdry J, Parry-Jones N, et al. Smdy of the association between cytochromes P450 2D6 and 2E1 genotypes and the risk of drug and chemical induced idiosyncratic aplastic anemia. Br J Haemotol 1999 104 266-270. 

Adverse reactions may include drowsiness ataxia dizziness slurred speech headache vertigo weakness impairment of visual accommodation euphoria overstimulation paradoxical excitement nausea vomiting diarrhea palpitations tachycardia various arrhythmias syncope hypotensive crises allergic/idiosyncratic reactions leukopenia acute nonthrombocytopenic purpura petechiae ecchymoses eosinophilia peripheral edema fever hyperpyrexia chills angioneurotic edema bronchospasm oliguria anuria anaphylaxis erythema multiforme exfoliative dermatitis stomatitis proctitis Stevens-Johnson syndrome bullous dermatitis paresthesias agranulocytosis aplastic anemia thrombocytopenic purpura. 

Carbamazepine Dose-related double vision, vertigo, gastrointestinal disturbance Idiosyncratic agranulocytosis, Stevens-Johnson syndrome, aplastic anemia... 

Considerable concern exists regarding the occurrence of idiosyncratic blood dyscrasias with carbamazepine, including fatal cases of aplastic anemia and agranulocytosis. Most of these have been in elderly patients with trigeminal neuralgia, and most have occurred within the first 4 months of treatment. The mild and persistent leukopenia seen in some patients is not necessarily an indication to stop treatment but requires careful monitoring. The most common idiosyncratic reaction is an erythematous skin rash other responses such as hepatic dysfunction are unusual. 

Chloramphenicol commonly causes a dose-related reversible suppression of red cell production at dosages exceeding 50 mg/kg/d after 1-2 weeks. Aplastic anemia, a rare consequence (1 in 24,000 to 40,000 courses of therapy) of chloramphenicol administration by any route, is an idiosyncratic reaction unrelated to dose, although it occurs more frequently with prolonged use. It tends to be irreversible and can be fatal. 

In some drug reactions, several of these hypersensitivity responses may present simultaneously. Some adverse reactions to drugs may be mistakenly classified as allergic or immune when they are actually genetic deficiency states or are idiosyncratic and not mediated by immune mechanisms (eg, hemolysis due to primaquine in glucose-6-phosphate dehydrogenase deficiency, or aplastic anemia caused by chloramphenicol). 

Anemias Hemolytic anemia occurs in patients with low levels of glucose 6-phosphate dehydrogenase3 (see p. 351). Other types of anemia occurring as a side effect of chloramphenicol include reversible anemia, which is apparently dose-related and occurs concomitantly with therapy, and aplastic anemia, which is idiosyncratic and usually fatal. [Note Aplastic anemia is independent of dose and may occur after therapy has ceased.]... 

Blood dyscrasias, mostly dose independent, are among the most important allergic-type adverse reactions to drugs. Aplastic anemia is a serious but rare (presumably) idiosyncratic reaction. It has been reported in association with chloramphenicol, quinacrine, phenylbutazone, mephenytoin, gold compounds, and potassium chlorate. Hemolytic anemia, thrombocytopenia, and agranulocytosis may result from an unusual, acquired sensitivity to a variety of widely used drugs including aminopyrine, phenylbutazone, phenothiazines, propylthiouracil, diphenylhydantoin, penicillins, chloramphenicol, sulfisoxazole, and tolbutamide. 

A second, more serious, type of bone marrow depression consists of aplastic anemia. Considered an idiosyncratic reaction rather than a toxic reaction, aplastic anemia occurs most commonly weeks to months after completion of therapy and is not dose related. In the most severe form of aplastic anemia, pancytopenia with an aplastic marrow is present. Prognosis is very poor because the anemia is usually irreversible. 

There is controversy about the risk of aplastic anemia with topical chloramphenicol. In a prospective case-control surveillance of aplastic anemia in a population of patients who had taken chloramphenicol for a total of 67.2 million person-years, 145 patients with aplastic anemia and 1226 controls were analysed. Three patients and five controls had been exposed to topical chloramphenicol, but two had also been exposed to other known causes of aplastic anemia. Based on these findings, an association between ocular chloramphenicol and aplastic anemia could not be excluded, but the risk was less than one per million treatment courses (38). In another study, a review of the literature identified seven cases of idiosyncratic hemopoietic reactions associated with topical chloramphenicol. However, the authors failed to find an association between the epidemiology of acquired aplastic anemia and topical chloramphenicol. Furthermore, after topical therapy they failed to detect serum accumulation of chloramphenicol by high performance hquid chromatography. They concluded that these findings support the view that topical chloramphenicol was not a risk factor for dose-related bone marrow toxicity and that calls for abolition of treatment with... 

Adverse events are sometimes termed type A (usually pharmacologically predictable, relatively frequent, seldom fatal and usually identified during clinical trials) or type B (unpredictable idiosyncratic reactions which are usually infrequent but can be very serious or fatal) (Rawlins and Thompson, 1977 Venning, 1983). Postmarketing ADR monitoring usually identifies the more serious, type B reactions. The sample size needed in clinical trials to detect differences between an incidence rate of 1/10 000 and 2/10 000 is about 306 000 patients (e.g. for a placebo comparison of chloramphenicol-induced aplastic anemia, which occurs in 1/30 000 Lasagna, 1983). Clinical trials at this scale are simply impractical. 

By most reports, idiosyncratic drug-induced hematologic disorders are rare. Relatively few epidemiologic studies have addressed the actual incidence of these adverse reactions. A report from The Netherlands estimated the incidence of drug-associated agranulocytosis as 1.6 to 2.5 cases per million inhabitants per year. Similar results were found in epidemiologic studies conducted in Thailand and BraziU Older data from a study conducted in Europe and Israel estimated the incidences of aplastic anemia and agranulocytosis to be 0.5 and 3.1 cases per million per year, respectively. ... 

Aplastic anemia This is a rare idiosyncratic reaction (approximately one case in 25,000-40,000 patients treated). It is usually irreversible and may be fatal. 

Gastric upset from CBZ may be diminished by taking the drug after meals. Common toxicities include blurred vision, dizziness, drowsiness, and ataxia. Tremor, depression, hyponatremia, and cardiac disturbances are seen at high serum concentrations. Idiosyncratic rashes are common rarer severe idiosyncratic effects include aplastic anemia, agranulocytosis, thrombocytopenia, and jaundice. Therefore, patients receiving CBZ should have periodic blood count determinations and liver function tests. Both CBZ and oxcarbazepine can reduce plasma 25-hydroxy vitamin D levels (45). CBZ increases levels of phenytoin and decreases levels of... 

All medications suspected to be possible triggers for the disease should be discontinued. Supportive measures, especially blood transfusions, are often necessary for treatment of anemia and bleeding complications. Drug-induced aplastic anemia is treated like the idiosyncratic form of the disease, and responds to therapy at about the same rate. Overall, immtmosuppressive therapy produces significant improvement in more than half of all patients younger individuals have a considerably better prognosis than those who are older than 45 years (Young et al. 2008). 

Chloramphenicol causes two distinct forms of toxicity in humans. The most serious form is an irreversible aplastic anaemia. This rare idiosyncratic response (the incidence is 25,000-60,000) may have an immunological component however, the meehanism of chloramphenicol-induced aplastic anemia remains unknown. Neither a dose-response relationship nor a threshold dose for the induction of aplastic anaemia has been established. Aplastic anemia is associated with reduced numbers of erythrocytes, leukocytes, and platelets (pancytopaenia), with resultant bleeding disorders and secondary infections. The condition tends to be irreversible and fatal. By comparison, leukemia may be a sequel of hypoplastic anemia. Because thiamphenicol and florfenicol lack the p-nitro moiety, they do not induce irreversible aplastic anemia in humans. 

Several drugs marketed currently have exhibited problems with toxicity or tetratoge-nicity. Hepatotoxicity, aplastic anemia, Stevens-Johnson syndrome, and neurotoxicity have been concerns cited frequently. Idiosyncratic reactions involving hematologic and dermatologic systems have proved fatal in a few cases. Considerable research effort has been directed toward identifying novel pharmaceutical moieties with a broad spectrum of efficacy and fewer side effects. 

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