Review Question - QID 107109

Gardos channel blockers are used to treat sickle cell disease by blocking the efflux of potassium and water from red blood cells, thus preventing RBC dehydration and reducing the frequency of vaso-occlusive events.

Both the K+/Cl- cotransporter and the Ca2+ activated potassium channel (also known as the Gardos channel) are important in the process of red blood cell dehydration. Both of these transporters are overly-active in permanently sickled cells, and, as such, most irreversibly sickled cells are dehydrated. Gardos channel blocking agents have been developed to prevent this efflux of potassium from the cell and block one pathway for RBC dehydration.

Mehta et al. note that treatment of sickle cell disease is multifactorial. Infection risk is high after splenic infarction that occurs at 2-4 years of age, often requiring prophylactic antibiotics and emphasis on immunization against encapsulated organisms. Chronic transfusion therapy is often indicated for stroke prevention, as is pain management during occlusive crises. Finally, careful monitoring for acute chest syndrome is of utmost importance, followed by aggressive respiratory supportive care when it occurs.

A phase II trial looking at the efficacy and safety of senicapoc, a potent Gardos-channel blocker, was performed by Ataga et al. They found that treatment with senicapoc significantly increased hemoglobin levels from baseline when compared with placebo and was well-tolerated by patients. Secondary endpoints, including percentage of dense RBCs, reticulocytes, lactate dehydrogenase, and indirect bilirubin showed significant decreases as well.

Illustration A is a representation of RBC sickling and how it leads to occlusive disease. Illustration B displays the role of the K+/Cl- co-transporter and the Gardos channel in RBC dehydration and sickling. Illustration C displays a classic blood smear from a patient with sickle cell disease.

Incorrect Answers:
Answer 2: This is the mechanism of action of hydroxyurea, which is the first-line agent of choice to reduce the frequency of events such as pain crises, acute chest syndrome, or stroke. HbF is the major form of prenatal hemoglobin and falls to a level of <1% by 6-12 months of age, explaining why children with sickle cell disease usually develop symptoms during this time period.
Answer 3: Though Gardos channel blockers do prevent RBC dehydration, it is by preventing potassium, not calcium, efflux.
Answers 4 and 5: These do not describe the mechanism of action of Gardos channel blockers.