A Textbook of Clinical Pharmacology and Therapeutics

bone 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.

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.Hydroxocobalaminis preferred, given as an initial
  loading dose followed by three monthly maintenance treat-
  ment for life.

Cellular mechanism of action

Vitamin B 12 is needed for normal erythropoiesis and for neu-

ronal 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 B 12

is also involved in the control of folate metabolism, and B 12

and folate are required for intracellular nucleoside synthesis.

Deficiency of vitamin B 12 ‘traps’ folate as methylene tetra-

hydrofolate, 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 B 12. Following total

gastrectomy liver stores (1–10 mg) are adequate for 3–5 years,

following which there is an increasing incidence of vitamin B 12

deficiency. The daily vitamin B 12 loss is 0.5–3μg, which results

mainly from metabolic breakdown, and 2–3μg is absorbed

daily from the diet. Vitamin B 12 is complexed with intrinsic fac-

tor (secreted from the gastric parietal cells). Intrinsic factor is a

HAEMATINICS– IRON, VITAMINB 12 ANDFOLATE 391

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 gastro-
  intestinal 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 non-
  compliance 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 (cyanocobal-
amin), hydroxyl (hydroxocobalamin) or methyl (methylcobal-
amin) group. These forms are interconvertible. Sources of
vitamin B 12 include liver, kidney heart, fish and eggs.

Use

Replacement therapy is required in vitamin B 12 deficiency
which may be due to:

• malabsorption secondary to gastric pathology (Addisonian
  pernicious anaemia, where parietal cells are destroyed by an

Levodopa

3-O-methyl-

dopa

Diet

SAM

SAH

THF

Methyl-

THF

4

2

1. COMT and other methyl-
   transferases


2. Methylene-THF-reductase


3. Methionine synthase


4. Cystathionine ß-synthase

SAM: S-adenosylmethionine

SAH: S-adenosylhomocysteine

THF: Tetrahydrofolate

Vitamin B 12

Methylene-

THF

Homocysteine

Methionine

3 1

Figure 49.2:Role of vitamin B 12 and folate in homocysteine –

methionine cycling.