PHAR: Haematinics

Question 1

• What are the three categories of anemia?
  
  • What are the ranges (in fL) for each of these?
  • What are some causes of these types of anaemia?

Answer 1

• Microcytic.
  
  • <80 fL.
  • Iron deficiency.
• Normocytic.
  
  • 80-100 fL.
  • Acute haemorrhage.
  • Renal failure due to problems with erythropoietin.
• Macrocytic.
  
  • >100 fL.
  • Vitamin B12/folate deficiency.
  • Methotrexate toxicity.

Question 2

• Is iron absorbed primarily in ferrous or ferric state?
• What clinical implications does this have when someone taking iron supplements are on antacids?
  
  • What other groups (two) of substances can lead to problems?

Answer 2

• Ferrous (Fe²⁺).
• Antacids lead to oxidation to Fe³⁺.
  
  • Ferric form results in unabsorbable salts and complexes to form.
  • Lower absorption.
• I: Antibiotics.
  
  • Tetracyclines and fluoroquinolones.
  • Complexes form.
• II: Food.
  
  • Forms complex with food.
  • ADVISE TO TAKE AWAY FROM FOOD.

Question 3

• How is iron supplementation usually done?
• Sometimes this is either too slow in replacing iron, or the doses required are intolerable to patient. What then?

Answer 3

• Oral is sufficient for most purposes.
• Parenteral IV administration is required (with sugars.
  
  • Fe-sucrose (all of them are Fe-[something]-ose).

Question 4

What are five adverse side effects of taking iron?

Answer 4

• Pain.
• Nausea.
• Dyspepsia.
• Constipation.
• Loose bowel motions.

Question 5

• Iron overdose can be very serious and poisonous, and lead to multisystem failure. Which particular group of people does this occur in commonly?
• Biochemically, why can too much iron cause problems?
• What is a common early side effect?

Answer 5

• Children.
• Catalyse redox reactions that generate free radicals.
• GI irritation.

Question 6

Fill in the diagram.

Answer 6

• G-CSF: Neutrophil progenitor cell → neutrophil.
• TPO: Megakaryocyte → platelet.
• EPO: Erythroid progenitor cell → RBC.
• M-CSF (macrophage CSF): monocyte progenitor cell → monocyte.

Question 7

Name three causes of megaloblastic anaemia.

Answer 7

• Vit B12 deficiency.
• Folate deficiency.
• Methotrexate toxicity.

Question 8

Hypersensitivity reactions to iron are rare, but do occur. What are some signs/symptoms? (2 points)

Answer 8

• General feeling of being unwell.
• Dramatic drop in blood pressure.

Question 9

What is a risk factor for folic acid deficiency?

Answer 9

Alcoholic diet.

Question 10

Describe the mechanism by which folate is converted to tetrahydrofolate.

Answer 10

• Folic acid converted to dihydrofolic acid, and then to tetrahydrofolate, both times via DHFR.
• Decorating pteridine component with hydrogen ions.
  
  • Adds 2 protons, and then adds 2 more.

Question 11

C1 groups in ____ and ____ derived from folate intermediates

Answer 11

C1 groups in purines and thymidine derived from folate intermediates

Question 12

• In the context of tetrahydrofolic acid, what is a C1 group?
  
  • What can a C1 group be?

Answer 12

• A one carbon group added to THF acid.
  
  • -CHO.
  • -CH₂-.
  • -CH₂=.
  • -CH3.

Question 13

Describe the folate acid deficiency mechanism, in broad terms.

Answer 13

• Impaired folate conversion → less nucleic acid synthesis.
• Delayed nuclear maturation and cellular reproduction.
  
  • Cells produced in lower numbers → accumulate larger contents.

Question 14

• What is the replacement for folic acid?
  
  • What is the dosing.
• What are the adverse side effects.

Answer 14

• Oral folic acid.
  
  • Daily.
• NONE.

Question 15

In which group is folic acid supplementation important in?

Answer 15

• Pregnant women.
  
  • Without it, can lead to neural tube defects.

Question 16

Broadly speaking, what is the MOA of methotrexate?

Answer 16

• Inhibitor of the enzyme that converts folic acid to dihydrofolic acid.
• Structurally similar to folic acid.
  
  • “DHFR gets confused and doesn’t know which one to put the protons on.” - David Joyce.
  • Stops DHFR at both stages of the folic acid to tetrahydrofolic acid process.

Question 17

• What is required for methotrexate toxicity to progress to megaloblastosis?
• The loss of what kind of cell gives away that MTX toxicity has occurred.

Answer 17

• Toxicity leads to megaloblastosis IF SUSTAINED.
  
  • Long time before anaemia that arises from this phenomenon becomes apparent.
• Loss of short-lived cells.
  
  • Neutrophils.
  • Platelets.
  • Enterocytes (line the gut).

Question 18

Giving lots of folate supplementation to counter MTX toxicity works, in theory. However, an alternate supplementation which is one of the downstream products of folic acid (and hence will have greater clinical effects) is used instead. What is it?

Answer 18

• Folinic acid.
  
  • 5-formyl-tetrahydrofolic acid.

Question 19

• True/false: dietary B12 deficiency is common?
• How is B12 deficiency most commonly caused?
• Describe the structure of the cobalamin/vit B12 molecule.

Answer 19

• False.
  
  • B12 is so abundantly available that dietary deficiency is RARE.
• More commonly through malabsorption.
• Structure:
  
  • Corin ring at the centre.
  • Cobalt attached.

Question 20

Describe the MOA of vitamin B12.

Answer 20

• Catalyses removal of methyl group: 5-methylhydrofolate → tetrahydrofolate.
• Homocysteine gains the methyl group; converted to methionine.
• Reduced THF → reduced DNA synthesis.
• Cobalamine has cofactor functions in other reactions.

Question 21

• What is a common mechanism by which B12 isn’t being absorbed?
• What can cause this problem?

Answer 21

NOT ABSORBING B12.

• Stomachs not producing intrinsic factor (IF).
  
  • IF binds B12 to carry it through gut to bind intrinsic factor receptors on distal ileum.
  • Absorption across gut wall.
• Problems with absorption:
  
  • Autoimmune.
  • Chronic gastritis.
• Given as hydroxocobalamine PARENTERALLY.

Question 22

• Describe the treatment, its administration, lifespan and dosing, for replacement of vitamin B12.
• What adverse side effects are there?

Answer 22

• Parenteral injection of hydroxycobalamine.
  
  • Intramuscular injection.
• Long-lived.

DOSING

• Weekly x 4.
• Once repleted, only need injections 1-3 months lifelong.
• Virtually no side effects.

Question 23

• Erythropoietin is a ____ hormone derived in the __x__.
  
  • Clinical relevance in the context of __x__?
• What is the method of administration?

Answer 23

• Erythropoietin is a peptide hormone derived in the kidneys.
  
  • Chronic renal failure can lead to anemia.
• Subcutaneous injection.

Question 24

EPO is broken down quite quickly. How is this problem avoided when treating people?

Answer 24

• Modified recombinant forms of EPO with longer half-lifes are used.
  
  • They have a longer duration in the body.

Question 25

• Filgrastim is a recombinant form of ____-_ _ _ that stimulates the conversion of neutrophil progenitor cell (precursors to neutrophils) to neutrophils.
• How is it administered?
• What are the clinical applications of filgrastim?

Answer 25

• Filgrastim = recombinant human G-CSF.
  
  • Human G-CSF produced in the bone marrow.
  • Human G-CSF is a 175 aa glycoprotein.
• Administered via injection.

CLINICAL APPLICATIONS

• Cancer chemotherapy leads to suppressed myeloid cell growth.
• Assist early reconstitution of leukocyte population after bone marrow transplantation.

Question 26

• What does romiplostim do?
  
  • What condition/s is/are it suitable for?

Answer 26

• Thrombopoietin-mimetic (Emulate platelet stimulating effects of thrombopoietin).
  
  • Binds & activates thrombopoetin receptor of megakaryocyte, to increase platelet production.
• Used in conditions where there’s inadequate platelet numbers.
  
  • ITP → isolated thrombocytopenic purpura.
  • More common: rebuilding platelet population after bone marrow transplant.

NOTE: not as common as recombinant EPO or filgrastim.