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Drugs and blood: haematopoiesis and haemostasis | Basicmedical Key

Drugs and blood: haematopoiesis and haemostasis





Due to the fact that blood is a liquid, it can sometimes be overlooked as an organ. Blood has multiple tasks: delivering oxygen and nutrients to tissue, taking waste products for disposal, embodying the immune response to pathogens and preventing haemorrhage after injury (which has the added benefit of creating a rapid barrier to the external environment when trauma has occurred). Blood accomplishes these tasks through the physiological processes of haematopoiesis (the production of blood cells) and haemostasis (the maintenance of vascular integrity). The first part of this chapter will discuss how blood cell production occurs and how this can be modified pharmacologically, whilst the second part of the chapter will discuss haemostasis, and the importance of pharmacology to prevent thrombosis or to modulate bleeding disorders.


The Haematopoietic System


The term haematopoiesis covers red blood cell generation (erythropoiesis), platelet production (thrombopoiesis) and white blood cell generation (leukopoiesis). Normal haematopoiesis requires certain exogenous substances (haematinic agents e.g. iron, folic acid, vitamin B 12 ) and various endogenous haematopoietic growth substances (e.g. colony-stimulating factors, erythropoietin, thrombopoietin). Thus dependent on these signals and other environmental cues, pluripotent stem cells residing in the bone marrow continually generate progeny that give rise to mature red blood cells, leukocytes and platelets (although recent data suggests that platelet production may also occur from megakaryocytes that have travelled to the pulmonary vascular bed) that egress from the bone marrow and circulate.


Erythropoiesis


The main function of the red blood cells (erythrocytes) is to carry oxygen.


Pathophysiology


The main disorders of erythropoiesis are the anaemias , which are classified according to the changes in the erythrocytes:




  • Hypochromic, microcytic anaemia (small red cells with low haemoglobin) due to deficiency of iron, the main cause being chronic blood loss.



  • Macrocytic anaemia (large red cells, few in number) due to deficiency of folic acid and/or vitamin B 12 .



  • Normochromic normocytic anaemia (fewer normal-sized red cells with normal haemoglobin) usually due to acute excessive destruction of red blood cells – haemolytic anaemia.



Haematinic agents


Iron


Iron is essential for haemoglobin production. A summary of its distribution in the body, transfer in the plasma, storage, movement between compartments and removal from the body is shown in Fig. 15.1 . Iron is readily available for transfer to the plasma from ferritin stores in the liver.




Fig. 15.1


The homeostasis of body iron.

The distribution and daily movement between tissues is shown; the darker the colour, the higher the concentration of iron.

GIT , gastrointestinal tract; Hb , haemoglobin; MNP , mononuclear phagocytes;

RBC , red blood cells.


The main preparation of iron is ferrous sulphate , given orally. A preparation for deep intramuscular use is iron sorbitol .


Unwanted effects


The main unwanted effect of iron salts is dose-related gastrointestinal (GI) tract disturbance: nausea, epigastric pain, abdominal cramps, diarrhoea. Acute iron toxicity with necrotizing gastritis and cardiovascular collapse can occur if large amounts of iron salts are ingested; chronic iron toxicity can follow repeated blood transfusions. Both are treated with an iron chelator: desferrioxamine .



Clinical uses of iron salts





  • For iron-deficiency anaemia caused by:




    • chronic blood loss, e.g. from excessive menstrual loss, haemorrhoids, etc.;



    • increased need for iron during pregnancy; or



    • reduced iron intake or absorption.





Folic acid and vitamin B 12


Both folic acid and vitamin B 12 are essential for DNA synthesis and cell proliferation.


Pathophysiology


Deficiencies of folic acid and/or vitamin B 12 lead to megaloblastic anaemia in which there are large, fragile, distorted red cells and abnormal precursors in the blood. Vitamin B 12 deficiency also causes neurological disease.


The principal cause of vitamin B 12 deficiency is decreased absorption of the vitamin either because of a lack of intrinsic factor (normally secreted by the stomach but missing in pernicious anaemia) or because of conditions that interfere with its absorption in the ileum. As there are large stores in the liver, the results of the deficiency can take a long time to manifest.


Folic acid deficiency results from dietary insufficiency, often associated with increased demand.


Folic acid


Folic acid (pteridine + para -aminobenzoic acid + glutamic acid) is essential for DNA synthesis and cell proliferation.


Actions


Folates, in the tetrahydrofolate (FH 4 ) polyglutamate form, are cofactors in the synthesis of purines and pyrimidines, being particularly important in thymidylate synthesis ( Fig. 15.2 ).




Fig. 15.2


Simplified diagram of the role of a folate in thymidylate synthesis.

(1) Folate is reduced to dihydrofolate (FH 2 ) by dihydrofolate reductase (DHFR). (2) Dihydrofolate (FH 2 ) is reduced to tetrahydrofolate (FH 4 ) by DHFR. (3) The FH 4 functions as a carrier of a one-carbon unit, providing the methyl group necessary for (4) the conversion of 2’deoxyuridylate (DUMP) to 2’deoxythymidylate (DTMP) by thymidylate synthetase. During the transfer of the one-carbon unit, FH 4 is oxidized to FH 2 , which must be reduced by DHFR to FH 4 (step 2) before it can act again. The thymidylate synthetase action is rate limiting in DNA synthesis. Note that in all the actions of folates it is the polyglutamate form that is most active.


Pharmacokinetic aspects


Folic acid is absorbed by active transport into intestinal cells where it is reduced by dihydrofolate reductase to FH 4 and then methylated to methyl-FH 4 which passes into the plasma. Eventually extra glutamates are added to give the active polyglutamate form.


Unwanted effects


These do not occur. However if folic acid alone is given in vitamin B 12 deficiency, the blood picture may improve, but other lesions (e.g. neurological) will not improve.


Vitamin B 12


Actions


Vitamin B 12 is important in reactions that enable folate to function in thymidylate synthesis ( Fig. 15.2 ). The reactions convert 5-methyl-FH 4 (a functionally inactive form of folate carried in the plasma) to the form of folate (FH 4 ) that can carry the one-carbon unit necessary for the formation of 2′deoxythymidylate (DTMP) from 2′deoxyuridylate (DUMP) ( Fig. 15.2 ). The mechanism of action is shown in Fig. 15.3 .




Fig. 15.3


The role of vitamin B 12 in reactions necessary for the eventual synthesis of thymidylate.

Methyl-FH 4 enters cells from the plasma by carrier. The methyl group is transferred to homocysteine to form methionine via vitamin B 12 , which is bound to a methyltransferase (not shown). Methionine donates the methyl group to FH 4 .

DUMP , 2’Deoxyuridylate.


Administration


Vitamin B 12 is given intramuscularly and is stored in the liver.


Unwanted effects


There are none.


Mar 31, 2020 | Posted by in PHARMACY | Comments Off on Drugs and blood: haematopoiesis and haemostasis
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