A Textbook of Clinical Pharmacology and Therapeutics

●Haematinics – iron, vitamin B 12 and folate 389

●Haematopoietic growth factors 392

●Coagulation factors and haemophilias A and B 394

●Aplastic anaemia 395

●Idiopathic thrombocytopenic purpura 395

CHAPTER 49

ANAEMIA AND OTHER

HAEMATOLOGICAL DISORDERS

HAEMATINICS – IRON, VITAMIN B 12 AND

FOLATE

IRON

Biochemistry and physiology

Iron plays a vital role in the body in many proteins including
transport proteins (e.g. haemoglobin, myoglobin) and enzymes
(e.g. CYP450s, catalase, peroxidase, metalloflavoproteins). It is
stored in the reticulo-endothelial system and bone marrow. The
total body iron content is 3.5–4.5 g in an adult, of which about
70% is incorporated in haemoglobin, 5% in myoglobin and
0.2% in enzymes. Most of the remaining iron (approximately
25%) is stored as ferritin or haemosiderin. About 2% (80 mg)
comprises the ‘labile iron pool’ and about 0.08% (3 mg) is
bound to transferrin (a specific iron-binding protein).

Pharmacokinetics

Gastro-intestinal (GI) absorption is the primary mechanism
controlling total body iron. This remains remarkably constant
(1–1.4 mg/day) in healthy individuals despite variations in
diet, erythropoiesis and iron stores. Iron absorption occurs in
the small intestine and is influenced by several factors:

1. The physico-chemical form of the iron:
   (a)Inorganic ferrous iron is better absorbed than ferric
   iron.
   (b)Absorption of iron from the diet depends on the
   source of the iron. Most dietary iron exists as
   non-haem iron (e.g. iron salts) and is relatively poorly
   absorbed (approximately 5–10%), mainly because it is
   combined with phosphates and phytates (in cereals).
   Haem iron is well absorbed (20–40%).
   2.Factors increasing absorption:
   (a)Acid: e.g. gastric acid and ascorbic acid facilitate iron
   absorption.
   (b)Ethanol increases ferric but not ferrous iron absorption.

3.Factors reducing iron absorption:

(a)Partial gastrectomy reduces gastric acid and iron

deficiency is more common than vitamin B 12

deficiency following partial gastrectomy.

(b)Malabsorption states, e.g. coeliac disease.

(c)Drug–iron binding interactions in the GI tract;

tetracyclines chelate iron, causing malabsorption of

both agents; oral bisphosphonates and magnesium

trisilicate reduce iron absorption.

Disposition of iron

Iron in the lumen of the gut is transported across the intes-

tinal membrane either directly into plasma or is bound by

mucosal ferritin. A negative regulator of gastro-intestinal

mucosal absorption of iron (hepcidin) synthesized by the liver

may contribute to the anaemia of chronic disease. Iron is trans-

ported in plasma by transferrin, one molecule of which binds

two atoms of iron. The iron is transferred to cells (e.g. red-cell

precursors in the bone marrow) by transferrin binding to trans-

ferrin receptors followed by endocytosis. The iron dissociates

from transferrin in the acidic intracellular environment. When

red cells reach the end of their life-span, macrophages bind the

iron atoms released, which are taken up again by transferrin.

About 80% of total body iron exchange normally takes place

via this cycle (Figure 49.1). Ferritin is the main storage form

of iron. It is a spherical protein with deeply located iron-

binding sites, and is found principally in the liver and the

reticulo-endothelial system. Aggregates of ferritin form

haemosiderin, which accumulates when levels of hepatic iron

stores are high.

Iron deficiency

Iron deficiency is the most common cause of anaemia and

although it is most common and most severe in Third World

countries, it is also prevalent in developed countries. Serum

iron concentration in iron-deficient patients falls only when

stores are considerably depleted. The total amount of transfer-

rin determines the total iron-binding capacity (TIBC) of plasma,