Page 612 - Basic _ Clinical Pharmacology ( PDFDrive )

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

reductase (Figure 33–3, section 3) and thereby serve as a source of The most common causes of vitamin B deficiency are perni-
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the tetrahydrofolate required for synthesis of the purines and dTMP cious anemia, partial or total gastrectomy, and conditions that affect
required for DNA synthesis. the distal ileum, such as malabsorption syndromes, inflammatory
Vitamin B deficiency causes the accumulation of homo- bowel disease, or small bowel resection. Strict vegans eating a diet
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cysteine due to reduced formation of methylcobalamin, which free of meat and dairy products may become B deficient.
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is required for the conversion of homocysteine to methionine Pernicious anemia results from defective secretion of intrinsic
(Figure 33–3, section 1). The increase in serum homocysteine factor by the gastric mucosal cells. Patients with pernicious anemia
can be used to help establish a diagnosis of vitamin B deficiency have gastric atrophy and fail to secrete intrinsic factor (as well as
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(Table 33–2). There is evidence from observational studies that hydrochloric acid). These patients frequently have autoantibodies
elevated serum homocysteine increases the risk of atherosclerotic to intrinsic factor. Historically, the Schilling test demonstrated
cardiovascular disease. However, randomized clinical trials have diminished absorption of radioactively labeled vitamin B , which
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not shown a definitive reduction in cardiovascular events (myocar- is corrected when intrinsic factor is administered with radioactive
dial infarction, stroke) in patients receiving vitamin supplementa- B , since the vitamin can then be normally absorbed. This test
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tion that lowers serum homocysteine. is now rarely performed due to use of radioactivity in the assay.
The other reaction that requires vitamin B is isomeriza- Vitamin B deficiency also occurs when the region of the dis-
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tion of methylmalonyl-CoA to succinyl-CoA by the enzyme tal ileum that absorbs the vitamin B –intrinsic factor complex is
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methylmalonyl-CoA mutase (Figure 33–2B). In vitamin B damaged, as when the ileum is involved with inflammatory bowel
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deficiency, this conversion cannot take place and the substrate, disease or when the ileum is surgically resected. In these situations,
methylmalonyl-CoA, as well as methylmalonic acid accumulate. radioactively labeled vitamin B is not absorbed in the Schilling
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The increase in serum and urine concentrations of methylmalonic test, even when intrinsic factor is added. Rare cases of vitamin
acid can be used to support a diagnosis of vitamin B deficiency B deficiency in children have been found to be secondary to
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(Table 33–2). In the past, it was thought that abnormal accumula- congenital deficiency of intrinsic factor or to defects of the recep-
tion of methylmalonyl-CoA causes the neurologic manifestations tor sites for vitamin B –intrinsic factor complex located in the
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of vitamin B deficiency. However, newer evidence implicates the distal ileum. Alternatives to the Schilling test include testing for
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disruption of the methionine synthesis pathway as the cause of intrinsic factor antibodies and testing for elevated homocysteine
neurologic problems. Whatever the biochemical explanation for and methylmalonic acid levels (Figure 33–2) to make a diagnosis
neurologic damage, the important point is that administration of of pernicious anemia with high sensitivity and specificity.
folic acid in the setting of vitamin B deficiency will not prevent Almost all cases of vitamin B deficiency are caused by malab-
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neurologic manifestations even though it will largely correct the sorption of the vitamin; therefore, parenteral injections of vitamin
anemia caused by the vitamin B deficiency. B are required for therapy. For patients with potentially revers-
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ible diseases, the underlying disease should be treated after initial
Clinical Pharmacology treatment with parenteral vitamin B . Most patients, however, do
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not have curable deficiency syndromes and require lifelong treat-
Vitamin B is used to treat or prevent deficiency. The most ment with vitamin B .
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characteristic clinical manifestation of vitamin B deficiency Vitamin B for parenteral injection is available as cyanocobalamin
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is megaloblastic, macrocytic anemia (Table 33–2), often with or hydroxocobalamin. Hydroxocobalamin is preferred because it is
associated mild or moderate leukopenia or thrombocytopenia (or more highly protein-bound and therefore remains longer in the cir-
both), and a characteristic hypercellular bone marrow with an culation. Initial therapy should consist of 100–1000 mcg of vitamin
accumulation of megaloblastic erythroid and other precursor cells. B intramuscularly daily or every other day for 1–2 weeks to replen-
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The neurologic syndrome associated with vitamin B deficiency ish body stores. Maintenance therapy consists of 100–1000 mcg
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usually begins with paresthesias in peripheral nerves and weak- intramuscularly once a month for life. If neurologic abnormalities
ness and progresses to spasticity, ataxia, and other central nervous are present, maintenance therapy injections should be given every
deficiency arrests 1–2 weeks for 6 months before switching to monthly injections. Oral
system dysfunctions. Correction of vitamin B 12
the progression of neurologic disease, but it may not fully reverse vitamin B 12 –intrinsic factor mixtures and liver extracts should not be
neurologic symptoms that have been present for several months. used to treat vitamin B deficiency; however, oral doses of 1000 mcg
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Although most patients with neurologic abnormalities caused by of vitamin B daily are usually sufficient to treat patients with perni-
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vitamin B deficiency have megaloblastic anemia when first seen, cious anemia who refuse or cannot tolerate the injections. After perni-
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occasional patients have few if any hematologic abnormalities. cious anemia is in remission following parenteral vitamin B therapy,
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Once a diagnosis of megaloblastic anemia is made, it must be the vitamin can be administered intranasally as a spray or gel.
determined whether vitamin B or folic acid deficiency is the
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cause. (Other causes of megaloblastic anemia are very rare.) This
can usually be accomplished by measuring serum levels of the FOLIC ACID
vitamins. The Schilling test, which measures absorption and uri-
nary excretion of radioactively labeled vitamin B , can be used to Reduced forms of folic acid are required for essential biochemical
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further define the mechanism of vitamin B malabsorption when reactions that provide precursors for the synthesis of amino acids,
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this is found to be the cause of the megaloblastic anemia. purines, and DNA. Folate deficiency is relatively common, even