Pharmacy & Therapeutics - April 2008 - (Page 238) CONTINUING EDUCATION CREDIT Pharmacological Management of Sickle Cell Disease Uche Anadu Ndefo, PharmD, BCPS; Angie Eaton Maxwell, PharmD; Huong Nguyen, PharmD Candidate; and Tochukwu L. Chiobi, PharmD Educational Objectives After reviewing this article, readers should be able to: I Define the basic hematological defect in sickle cell disease. I Identify the mechanisms of action and adverse events associated with standard treatment options. I Review the protocol for preventing stroke and infection in patients with sickle cell disease. I Identify treatment options currently under investigation. Pathogenesis Sickle cell disease is characterized by a structural abnormality in the beta-globin chain of the hemoglobin molecule within the red blood cells (RBCs). The sickle mutation is a single base change (GAT → GTT) in the sixth codon of exon-1 of the betaglobin gene on chromosome 11. This change leads to the synthesis of the beta-globin polypeptide of the hemoglobin molecule. This mutation causes the replacement of the normal glutamic acid with valine acid, thus resulting in the formation of the sickle cell hemoglobin (HbS). This hydrophobic aminoacid substitution causes the hemoglobin to take on a “sickle” shape when in a deoxygenated state. The ability of these sickled cells to adapt to their surroundings is impaired, especially in the microvasculature. These cells hemolyze prematurely, accounting for the chronic anemia frequently encountered by patients with SCD.5 The paucity of sickled cells in newborns with SCD led to the discovery that fetal hemoglobin (HgF) reduces the severity of SCD by preventing the formation of the hemoglobin S polymer.6 Fever, dehydration, hypoxia, acidosis, stress, and a cold environment may precipitate sickling, although a precursor event is not always identified.7,8 The pathophysiology of SCD is considerably complex, involving abnormalities of hemoglobin, the RBC’s membrane, er ythrocyte hydration, the endothelium, vascular tone, inflammatory responses, leukocytes, and coagulation. This forceful combination of factors results in cell interactions, generating hemolysis and microvascular obstruction, ultimately leading to damage of nearly all organ systems.9 Introduction Sickle cell disease (SCD) is the most common inherited blood disorder in the U.S., affecting about 72,000 Americans. It is also the most common inherited disease among AfricanAmericans and affects approximately one out of every 500 newborns. People of other races are also affected by SCD, with a rate of one of every 1,000 to 1,400 HispanicAmerican births.1 A significant prevalence of the mutation responsible for sickle cell has been reported among other ethnic groups such as those native to Italy, Greece, Turkey, Saudi Arabia, India, Pakistan, Bangladesh, China, and Cyprus.2 In 2004, 83,149 hospitalizations were attributable to SCD in the U.S., at a cost of almost $488 million.3 Episodes of pain, chronic hemolytic anemia, and severe infections are some of the common characteristics of this disease that begin in early childhood.4 Management of SCD is geared toward preventing complications and reducing the number of sickle cell crises. Risk Factors Dr. Ndefo and Dr. Maxwell are Assistant Professors of Pharmacy Practice in the College of Pharmacy and Health Sciences at Texas Southern University in Houston, Texas. They are also Drug Information Specialists at Harris County Hospital District in Houston. Huong Nguyen is a pharmacy student at Texas Southern University. Dr. Chiobi is a recent graduate of Texas Southern University. Two million people worldwide are carriers of or have the sickle cell trait. Carriers are usually asymptomatic and have a low percentage of sickle hemoglobin (HbS). Two parents who are carriers can both pass on the sickle cell trait to their offspring, resulting in SCD. There is a 50% chance with each pregnancy for the child of two sickle cell carriers to be born with the sickle cell trait, and there is a 25% chance for the child to be born with SCD (Figure 1). Accepted for Continuing Education Credit March 4, 2008. 238 P&T® • April 2008 • Vol. 33 No. 4
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