Clinical Pharmacology and Therapeutics

392 ANAEMIA AND OTHER HAEMATOLOGICAL DISORDERS
glycoprotein of molecular weight approximately 55 kDa which
forms a stable complex with vitamin B 12 . The complex passes
down the small intestine and binds to specific receptors on the
mucosa of the terminal ileum (at neutral pH and in the presence
of calcium) and is actively absorbed. Once in the circulation,
vitamin B 12 is transported by the beta globulin transcobalamin
II (TC II) to tissues, with its primary storage site being the
liver (90% body stores). Vitamin B 12 complexed with other
transcobalamins (TCI and III, which are alpha-globulins) probably
represent the major intracellular storage form. The normal
range of plasma vitamin B 12 concentration is 170–900 ng/L
(150–660 pmol/L). Vitamin B 12 is secreted into the bile,
but enterohepatic circulation results in most of this being
reabsorbed via the intrinsic factor mechanism.
FOLIC ACID
Uses
Folic acid is given to correct or prevent deficiency states and
prophylactically during pregnancy. It consists of a pteridine
ring linked to glutamic acid via p-aminobenzoic acid (PABA).
The richest dietary sources are liver, yeast and green vegetables.
Folate deficiency may be due to:
• poor nutrition – in children, the elderly or those with
alcoholism;
• malabsorption – caused by coeliac disease, sprue or
diseases of the small intestine;
• excessive utilization – in pregnancy, chronic haemolytic
anaemias (e.g. sickle cell disease) and leukaemias;
• anti-epileptic drugs (e.g. phenytoin).
The normal requirement for folic acid is about 200 μg daily.
In established folate deficiency, large doses (5–15 mg orally per
day) are given. If the patient is unable to take folate by mouth, it
may be given intravenously. Patients with severe malabsorption
may be deficient in both folic acid and vitamin B 12 , and administration
of folic acid alone may precipitate acute vitamin B 12 deficiency.
Such patients require replacement of both vitamins
concurrently. Many patients on chronic anticonvulsant therapy
develop macrocytosis without frank folate deficiency. Treatment
is by the addition of folic acid to the anticonvulsant regimen.
Cellular mechanism of action
Folic acid is required for normal erythropoiesis. Deficiency of
folic acid results in a megaloblastic anaemia and abnormalities
in other cell types. Folate acts as a methyl donor in biochemical
reactions, including the methylation of deoxyuridylic acid to
form thymidylic acid, as well as other reactions in purine and
pyrimidine synthesis.
Pharmacokinetics
Folate is present in food as reduced polyglutamates. These are
hydrolysed to monoglutamate, reduced and methylated to
methyltetrahydrofolate by the combined action of pteroylglutamyl
carboxypeptidase and tetrahydrofolate reductase. This
occurs in the proximal small intestine, the site of folate absorption
into the portal blood. About one-third of total body folate
(70 mg) is stored in the liver, representing only about four
months supply. The normal range for serum folate concentration
is 4–20 μg/L.
IRON AND FOLIC ACID THERAPY IN PREGNANCY
Pregnancy imposes a substantial increase in demand on maternal
stores of iron and folic acid. A pregnant woman during the
last trimester therefore requires approximately 5 mg of iron
daily. Most women are iron depleted by the end of the pregnancy
if they do not receive supplements. Requirements for
folic acid also increase by two- to three-fold during pregnancy.
Folate deficiency is associated with prematurity, low birth
weight for gestational age and neural-tube defects (Chapter 9).
In the UK, the usual practice is to give iron and folic acid
supplements throughout pregnancy. Folate supplementation
should be also be given before conception to women who are
attempting to become pregnant, in order to reduce the incidence
of neural-tube defects. High-dose prophylaxis (folate,
5 mg daily) is advised for women who have previously given
birth to a child with a neural-tube defect.
Key points
Vitamin B 12 and folate therapy
• Healthy subjects require 3–5 μg of vitamin B 12 and
200 μg of folate daily.
• Body stores of vitamin B 12 are 3 mg; folate stores are
approximately 200 mg.
• Vitamin B 12 and folate are absorbed from the small
intestine, and vitamin B 12 is specifically absorbed from
the terminal ileum.
• The most common cause of B 12 or folate deficiency is
dietary or malabsorption, or due to gastric surgery.
• Vitamin B 12 deficiency must not be inappropriately
treated with folate alone, as any associated
neurological damage may be irreversible.
• Drugs may cause vitamin B 12 (e.g. metformin) or folate
(e.g. phenytoin, other anti-epileptic drugs) deficiency.
PYRIDOXINE, RIBOFLAVIN
Sideroblastic anaemia with failure of incorporation of iron into
haem in the mitochondria, may respond to long-term pyridoxine
supplementation. Infrequently, red cell aplasia is due to
riboflavin deficiency and will respond to supplementation
with this vitamin (Chapter 35).
HAEMATOPOIETIC GROWTH FACTORS
Recombinant DNA technology has been used to synthesize
several human haematopoietic growth factors (Figure 49.3
shows an outline of haematopoiesis). Haematopoietic growth
factors now have a clear role in the treatment of many forms of
bone marrow dysfunction.
RECOMBINANT HUMAN ERYTHROPOIETIN
(ERYTHROPOIETIN AND DARBEPOETIN)
Erythropoietin is secreted as a glycosylated protein with a
mass of 34 kDa. About 90% of endogenous erythropoietin is