A Textbook of Clinical Pharmacology and Therapeutics

one marrow to produce red cells. The only advantages of
parenteral iron are the following:
• Iron stores are rapidly and completely replenished.
• There is no doubt about compliance.
• It is effective in patients with malabsorption.
Parenteral iron should therefore only be considered in the
following situations:
• malabsorption;
• genuine intolerance of oral iron preparations;
• when continued blood loss is not preventable and large
doses of iron cannot be readily given by mouth;
• failure of patient compliance;
• when great demands are to be made on a patient’s iron
stores (e.g. in an anaemic pregnant woman just before term).
IRON DEXTRAN AND IRON SUCROSE INJECTIONS
Use
These can be administered by deep intramuscular injection (to
minimize staining of the skin) or intravenously (anaphylactoid
reactions can occur (up 3% of patients) and a small test dose
should be given initially). Oral iron should be stopped 24
hours before starting parenteral iron therapy and not restarted
until five days after the last injection.
Key points
Iron replacement therapy
• In health, normal iron losses require the absorption of
0.5–1 mg (in males) and 0.7–2 mg (in menstruating
females) of iron.
• Ferrous iron is best absorbed from the small intestine.
• Iron deficiency is the most common cause of anaemia
(e.g. malabsorption, menstrual, occult or gastrointestinal
blood loss – always determine the cause).
• For iron deficiency, 100–200 mg of elemental iron
are given orally per day and continued until iron stores
are replete, usually within three to six months.
• Parenteral iron use is restricted to cases of noncompliance
or non-tolerance of oral preparations,
or malabsorption states.
• During erythropoietin therapy, supplemental iron is
given to support increased haem synthesis.
VITAMIN B 12
Vitamin B 12 is an organic molecule with an attached cobalt
atom. Linked to the cobalt atom may be a cyanide (cyanocobalamin),
hydroxyl (hydroxocobalamin) or methyl (methylcobalamin)
group. These forms are interconvertible. Sources of
vitamin B 12 include liver, kidney heart, fish and eggs.
Use
Replacement therapy is required in vitamin B12 deficiency
which may be due to:
• malabsorption secondary to gastric pathology (Addisonian
pernicious anaemia, where parietal cells are destroyed by an
HAEMATINICS – IRON, VITAMIN B 12 AND FOLATE 391
autoimmune reaction, so intrinsic factor is not produced,
resulting in vitamin B 12 deficiency; gastrectomy);
• intestinal malabsorption (e.g. Crohn’s disease or surgical
resection of the terminal ileum);
• competition for vitamin B 12 absorption by gut organisms
(e.g. blind loop syndrome due to a jejunal diverticulum or
other cause of bacterial overgrowth, infestation with the
fish tapeworm Diphyllobothrium latum);
• nutritional deficiency – this is rare and is limited to strict
vegans. The few such individuals who do develop
megaloblastic anaemia often have some co-existing
deficiency of intrinsic factor.
Vitamin B 12 replacement therapy is given by intramuscular
injection. Hydroxocobalamin is preferred, given as an initial
loading dose followed by three monthly maintenance treatment
for life.
Cellular mechanism of action
Vitamin B12 is needed for normal erythropoiesis and for neuronal
integrity. It is a cofactor needed for the isomerization of
methylmalonyl coenzyme A to succinyl coenzyme A, and for
the conversion of homocysteine into methionine (which also
utilizes 5-methyltetrahydrofolate, see Figure 49.2). Vitamin B12 is also involved in the control of folate metabolism, and B12 and folate are required for intracellular nucleoside synthesis.
Deficiency of vitamin B12 ‘traps’ folate as methylene tetrahydrofolate,
yielding a macrocytic anaemia with megaloblastic
erythropoiesis in the bone marrow, and possible neurological
dysfunction, i.e. peripheral neuropathy, subacute combined
degeneration of the spinal cord, dementia and optic neuritis.
Pharmacokinetics
Humans depend on exogenous vitamin B12. Following total
gastrectomy liver stores (1–10 mg) are adequate for 3–5 years,
following which there is an increasing incidence of vitamin B12 deficiency. The daily vitamin B12 loss is 0.5–3 μg, which results
mainly from metabolic breakdown, and 2–3 μg is absorbed
daily from the diet. Vitamin B12 is complexed with intrinsic factor
(secreted from the gastric parietal cells). Intrinsic factor is a
Methylene-
THF
2
THF
Methyl-
THF
1. COMT and other methyltransferases
2. Methylene-THF-reductase
3. Methionine synthase
4. Cystathionine ß-synthase
3
Diet
Methionine
Vitamin B 12
SAM
SAH
Homocysteine
4
1
Levodopa
3-O-methyldopa
SAM: S-adenosylmethionine
SAH: S-adenosylhomocysteine
THF: Tetrahydrofolate
Figure 49.2: Role of vitamin B 12 and folate in homocysteine –
methionine cycling.