Outlining Drug-Induced Anemia and Select Medications

Outlining Drug-Induced Anemia and Select Medications
NAAC Article Published: October 21, 2009

Anemia can be a consequence of nutritional deficiencies or chronic diseases, but it may also occur from the treatment of the disease itself. Several types of drugs have been reported to cause different forms of anemia, including aplastic anemia, megaloblastic anemia, hemolytic anemia, and anemia caused by blood loss, chronic inflammation or suppression of red blood cell production.1 This article profiles a range of medications which can lead to these types of anemia and describes the mechanisms at work so that you may be able to prevent or minimize drug-induced cases of anemia.

Hemolytic Anemia

Drug-induced immune hemolytic anemia (IHA) is an acquired form of hemolytic anemia. Autoimmune hemolytic anemias are typically acute disorders that can lead to rapid hemolysis and a precipitous decline in Hb/Hct. Drugs can produce varying degrees of hemolysis, ranging from mild to severe.

Drugs that can cause this type of hemolytic anemia include:2

* Cephalosporins (a class of antibiotics)
* Levodopa
* Methyldopa
* Penicillin and its derivatives
* Quinidine
* Some nonsteroidal anti-inflammatory drugs (NSAIDs)
* Ribavirin

Hemolytic anemia is a major side effect of ribavirin therapy in patients with Hepatitis C.3 For more information on this topic, please refer to NAACs Anemia Monograph: Anemia & Hepatitis C.

Inflammation, Bleeding and Iron Deficiency Anemia

A number of drugs cause intestinal bleeding with a possible result of iron deficiency anemia. For instance, drug-induced anemia may be the first symptom of GI bleeding in patients receiving treatment for rheumatoid arthritis (RA). Blood loss from the GI tract may result in significant morbidity and contribute to anemia in patients with RA who are taking NSAIDS.4
Medications Discussed

* Cephalosporins
* Levodopa
* Methyldopa
* Penicillin
* Quinidine
* Nonsteroidal anti-
inflammatory drugs (NSAIDs)
* Ribavirin
* Corticosteroids
* Warfarin
* Heparin
* Salicylate derivatives
* Angiotensin-converting enzyme (ACE) inhibitors
* angiotensin receptor blockers (ARB)
* Zidovudine
* Methotrexate
* Pyrimethamine
* Primidone
* Chloramphenicol
* Felbamate
* Chemotherapeutic agents

Studies have shown that up to 70% of patients taking long term NSAIDs develop small intestinal inflammation associated with blood and protein loss, and this intestinal inflammation may persist for up to 16 months after discontinuation of NSAIDs. Patients should be routinely questioned on their use of OTC preparations, many of which contain salicylate derivatives or NSAIDs.

ACE Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) are widely used for a range of indications, including hypertension, left venticular dysfunction, and diabetic nephropathy. Both ACE inhibitors and ARBs have been implicated in the exacerbation of anemia by the suppression of erythropoiesis and the induction of resistance to erythrpoietic therapy.5

There are conflicting reports on the potential effect of ACE inhibitors on erythropoiesis in dialysis patients. Several studies have found that these drugs do not affect the action of epoetin alfa, and that doses and Hb levels are similar among treated and control patients. Other reports, where no other cause of epoetin alfa hyporesponsiveness could be determined, concluded that ACE inhibitors decrease the effectiveness of epoetin alfa therapy.5 The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) guidelines recommend monitoring patients who are receiving concomitant epoetin alfa and ACE inhibitor therapies and adjusting the epoetin alfa dose as necessary to sustain a stable hemoglobin.5

HIV Drugs

Drugs used for the treatment of HIV or its complications can cause anemia. Zidovudine is a common cause of drug-induced anemia in HIV patients. Patients who develop zidovudine related anemia genrally present with a slow decline in hemoglobin level, usually developing 2-6 weeks after the start of therapy.6 For more information on this topic, please refer to NAACs Anemia Monograph: Anemia & HIV/AIDS.

Megaloblastic Anemia

Megaloblastic anemia is thought to be due to a defective metabolism of folate.7 A number of drugs, including methotrexate and pyrimethamine, lead to megaloblastic anemia by interference with dihydrofolate reductase.7 Anticonvulsant drugs, especially primidone, have also been known to cause megaloblastic anemia.

Aplastic Anemia

Drug-induced aplastic anemia is one of the few life-threatening reactions to drugs. Aplastic anemia is rare, but very serious when it does occur. The majority of reported cases have been associated with chloramphenicol, which has led to disuse as a first-line therapy, except in cases where the mortality of the disease being treated is high, and when there is no other alternative available.8 The antiseizure medication felbamate has also been associated with a marked increase in the incidence of aplastic anemia, and is only used in patients whose epilepsy is so severe that the risk of aplastic anemia is deemed acceptable.9 Many cancer chemotherapeutic agents have been reported to cause aplastic anemia.

Mitigating Use and Monitoring Patients

It is important for clinicians to recognize the types of drugs and drug classes that can cause anemia and to monitor patients for potential drug-induced anemias. Mitigating the use of drugs such as aspirin and NSAIDs, may help reduce anemia risk. However, using a specific treatment that can cause anemia may be unavoidable. Monitoring these patients for anemia symptoms is a vital component of their treatment. Many mild types of anemia can be easily treated, however, certain types of anemia may be severe, long lasting, and life threatening if not diagnosed and treated accordingly.
Check back regularly for upcoming resources covering drug-induced anemia. Contact NAAC for more information.
References

1. Lubran MM. Hematologic side effects of drugs. Ann Clin Lab Sci. 1989 Mar-Apr;19(2):114-21. Link.
2. National Library of Medicine. Medline Plus Medical Encyclopedia. Drug Induced Immune Hemolytic Anemia. Link. Accessed: September 27, 2009.
3. Jarvis SM, Thorn JA, Glue P. Ribavirin uptake by human erythrocytes and the involvement of nitrobenzylthioinosine-sensitive (es)-nucleoside transporters. Br J Pharmacol. 1998 Apr;123(

:1587-92. Link.
4. Bjarnason I, Hayllar J, MacPherson AJ, Russell AS. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology. 1993 Jun;104(6):1832-47. Link.
5. Macdougall IC. The role of ACE inhibitors and angiotensin II receptor blockers in the response to epoetin. Nephrol Dial Transplant. 1999 Aug;14(

:1836-41. Link.
6. Henry DH. Management of Anemia in a Zidovudine treated patient. Aids Patient Care 1991; 5(3):116-19. Link.
7. Girdwood RH. Drug Induced Anemias. Drugs. 1976;11(5):394-404. Link.
8. Malkin D, Koren G, Saunders EF. Drug-induced aplastic anemia: pathogenesis and clinical aspects. Am J Pediatr Hematol Oncol. 1990;12(4):402-10. Link. Accessed: September 27, 2009.
9. Meda Pharmaceuticals Inc. Felbatol Product Package Insert. Revised June 2008. Link.

Last Updated: October 21, 2009

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