Page 606 - Basic _ Clinical Pharmacology ( PDFDrive )

592 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

that regulate the proliferation and differentiation of hematopoi- vasodilation—can worsen the condition of patients with underly-
etic cells. Inadequate supplies of either the essential nutrients or ing cardiovascular disease.
the growth factors result in deficiency of functional blood cells. Iron forms the nucleus of the iron-porphyrin heme ring, which
Anemia, a deficiency in oxygen-carrying erythrocytes, is the most together with globin chains forms hemoglobin. Hemoglobin
common deficiency and several forms are easily treated. Sickle reversibly binds oxygen and provides the critical mechanism for
cell anemia, a condition resulting from a genetic alteration in oxygen delivery from the lungs to other tissues. In the absence of
the hemoglobin molecule, is common but is not easily treated. adequate iron, small erythrocytes with insufficient hemoglobin
It is discussed in the Box: Sickle Cell Disease and Hydroxyurea. are formed, giving rise to microcytic hypochromic anemia. Iron-
Thrombocytopenia and neutropenia are not rare, and some containing heme is also an essential component of myoglobin,
forms are amenable to drug therapy. In this chapter, we first con- cytochromes, and other proteins with diverse biologic functions.
sider treatment of anemia due to deficiency of iron, vitamin B ,
12
or folic acid and then turn to the medical use of hematopoietic Pharmacokinetics
growth factors to combat anemia, thrombocytopenia, and neutro-
penia, and to support stem cell transplantation. Free inorganic iron is extremely toxic, but iron is required for
essential proteins such as hemoglobin; therefore, evolution has
provided an elaborate system for regulating iron absorption,
■ AGENTS USED IN ANEMIAS transport, and storage (Figure 33–1). The system uses special-
ized transport, storage, ferrireductase, and ferroxidase proteins
IRON whose concentrations are controlled by the body’s demand for
hemoglobin synthesis and adequate iron stores (Table 33–1). A
peptide called hepcidin, produced primarily by liver cells, serves
Basic Pharmacology as a key central regulator of the system. Nearly all of the iron
Iron deficiency is the most common cause of chronic anemia. used to support hematopoiesis is reclaimed from catalysis of the
Like other forms of chronic anemia, iron deficiency anemia leads hemoglobin in senescent or damaged erythrocytes. Normally, only
to pallor, fatigue, dizziness, exertional dyspnea, and other gen- a small amount of iron is lost from the body each day, so dietary
eralized symptoms of tissue hypoxia. The cardiovascular adapta- requirements are small and easily fulfilled by the iron available
tions to chronic anemia—tachycardia, increased cardiac output, in a wide variety of foods. However, in special populations with

Sickle Cell Disease and Hydroxyurea

Sickle cell disease is an important genetic cause of hemo- extremely severe bone and joint pain. In the cerebral vascular
lytic anemia, a form of anemia due to increased erythrocyte system, it causes ischemic stroke. Damage to the spleen increases
destruction, instead of the reduced mature erythrocyte pro- the risk of infection, particularly by encapsulated bacteria such
duction seen with iron, folic acid, and vitamin B 12 deficiency. as Streptococcus pneumoniae. In the pulmonary system, there
Patients with sickle cell disease are homozygous for the aberrant is an increased risk of infection and, in adults, an increase in
β-hemoglobin S (HbS) allele (substitution of valine for glutamic embolism and pulmonary hypertension. Supportive treatment
acid at amino acid 6 of β-globin) or heterozygous for HbS and includes analgesics, antibiotics, pneumococcal vaccination, and
a second mutated β-hemoglobin gene such as hemoglobin C blood transfusions. In addition, the cancer chemotherapeutic
(HbC) or β-thalassemia. Sickle cell disease has an increased preva- drug hydroxyurea (hydroxycarbamide) reduces veno-occlusive
lence in individuals of African descent because the heterozygous events. It is approved in the United States for treatment of
trait confers resistance to malaria. adults with recurrent sickle cell crises and approved in Europe
In the majority of patients with sickle cell disease, anemia in adults and children with recurrent vaso-occlusive events. As
is not the major problem; the anemia is generally well com- an anticancer drug used in the treatment of chronic and acute
pensated even though such individuals have a chronically low myelogenous leukemia, hydroxyurea inhibits ribonucleotide
hematocrit (20–30%), a low serum hemoglobin level (7–10 g/dL), reductase and thereby depletes deoxynucleoside triphosphate
and an elevated reticulocyte count. Instead, the primary problem and arrests cells in the S phase of the cell cycle (see Chapter 54).
is that deoxygenated HbS chains form polymeric structures that In the treatment of sickle cell disease, hydroxyurea acts through
dramatically change erythrocyte shape, reduce deformability, poorly defined pathways to increase the production of fetal
and elicit membrane permeability changes that further promote hemoglobin γ (HbF), which interferes with the polymerization of
hemoglobin polymerization. Abnormal erythrocytes aggregate HbS. Clinical trials have shown that hydroxyurea decreases pain-
in the microvasculature—where oxygen tension is low and ful crises in adults and children with severe sickle cell disease. Its
hemoglobin is deoxygenated—and cause veno-occlusive dam- adverse effects include hematopoietic depression, gastrointesti-
age. In the musculoskeletal system, this results in characteristic, nal effects, and teratogenicity in pregnant women.