A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

CHAPTER 49
ANAEMIA AND OTHER
HAEMATOLOGICAL DISORDERS
● 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
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 intestinal
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 transported
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 transferrin
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 ironbinding
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 transferrin
determines the total iron-binding capacity (TIBC) of plasma,