Drugs For Anemia

Front 1

There are two forms of iron available in the diet:

Back 1

(1) heme iron (found in meat, fish & poultry), which has the greatest
bioavailability; and,
(2) nonheme iron (found in vegetables & dietary supplements).
Absorption of nonheme iron is affected by:
(a) phosphates which DECR absorption; and,
(b) ascorbic acid and meat which INCR absorption.

Front 2

Iron is best absorbed in its.......(what form)

Back 2

Iron is best absorbed in its ferrous (Fe2+) form, however, dietary iron is in
the ferric (Fe3+) form which is not absorbed. Ferric iron is ionized by
stomach acid and then reduced to the ferrous form. The ferrous form is actively taken up primarily in the duodenum but absorptive processes of
the mucosa limit the amount of iron absorbed.

Front 3

Internal exchange of iron

Back 3

a. Within the mucosal cells, ferrous iron is oxidized to ferric iron which
forms a complex with transferrin, a ß1-glycoprotein with two binding sites
for ferric iron.
b. This complex binds to specific receptors in the plasma membrane
c. and is taken up by receptor-mediated endocytosis.
d. Iron dissociates inside the cell
and transferrin is returned to the
cell surface where it is released
to function again.
e. If iron is plentiful, then there are
fewer transferrin receptors on
the surface of cells. This
prevents iron-replete cells from
receiving excess iron.

Front 4

Storage forms of iron include:

Back 4

1) essential iron-containing
compounds (hemoglobin, myoglobin, enzymes)
(2) ferritin (combination of ferric iron with apoferritin)
(3) hemosiderin (aggregated ferritin)

Front 5

Sites of iron storage include:

Back 5

(1) the reticuloendothelial system
(2) hepatocytes.

Very little iron is lost; about 10%/year in men, more in women due to
menstruation. Absorption of iron determines the body’s iron content (see
above).

Front 6

Causes of anemia

Back 6

a. Inadequate dietary intake especially during growth in children and in
menstruating and pregnant females
b. Malabsorption
c. Blood loss

Front 7

Symptoms of iron deficiency anemia

Back 7

a. Feelings of weakness and lassitude
b. Headache
c. Dizziness
d. Palpitations; chest pain
e. Decreased exercise tolerance; shortness of breath

Front 8

Oral iron

Back 8

Ferrous salts (e.g., sulfate) are the treatment of choice.

Front 9

Absorption of oral Iron, therapeutic effect

Back 9

2) Absorption of ferrous salts is optimal during fasting.
(3) Evaluating therapeutic outcomes
(a) hemoglobin recovers in 1–2 months;
(b) replenishment of iron stores may require many (3–6) months.

Front 10

Untoward effects of oral iron

Back 10

Untoward effects of oral iron are confined to the gastrointestinal
tract
(a) heartburn
(b) constipation or diarrhea
(c) nausea (more prevalent at higher doses)
(d) upper abdominal pain (more prevalent at higher doses)

Front 11

Drug interactions of Oral Iron

Back 11

(a)  gastric pH (e.g. antacids, proton-pump inhibitors, H2-
receptor antagonists) --DECR absorption of iron salts
(b) Iron can interfere with absorption of many drugs -->Avoid
concurrent administration, separate doses by >2 hours.

Front 12

Therapy with parenteral iron
(1) Indications

Back 12

(a) Patients in whom GI absorption is prevented by disease
(b) Patient who cannot tolerate orally administered iron
(c) Hemodialysis patients (Sodium ferric gluconate and iron
sucrose)

Front 13

Therapy with parenteral iron

Iron Dextran info

Back 13

i) Administered im or iv
ii) It is a complex of ferric oxyhydroxide with polymerized
dextran
iii) The complex must be phagocytized by reticuloendothelial
cells before iron becomes available
iv) Can cause anaphylaxis. Although rare, it can be fatal
despite treatment.

Front 14

Therapy with parenteral iron

Sodium Ferric gluconate and iron sucrose

Back 14

i) Better tolerated than iron dextran
ii) Delivered to transferrin more readily
iii) Lower risk of anaphylactic reactions

Front 15

Iron poisoning

Back 15

Large amounts of ferrous salts by mouth are toxic in adults but
most deaths occur in children between ages 12 and 24 months

Front 16

Iron poisoning

Signs and symptoms

Back 16

i) abdominal pain
ii) diarrhea
iii) vomiting brown or bloody stomach contents with pills
iv) lassitude & drowsiness
v) pallor or cyanosis
vi) hyperventilation (due to acidosis)
vii) cardiovascular collapse
viii) Death can occur within 6 hours or be delayed 12-24 hours
with a period of apparent recovery in between.

Front 17

Iron poisoning

Treatment

Back 17

Treatment includes emesis & lavage with sodium bicarbonate to precipitate iron

Front 18

Iron poisoning

If plasma concentration of iron > 3.5 mg/L,

Back 18

If plasma concentration of iron > 3.5 mg/L, deferoxamine (IM or IV)
is indicated.
(a) Deferoxamine has a high affinity for ferric iron.
(b) Once bound with iron, feroxamine is excreted in the urine
Contraindicated in renal insufficiency and anuria.
(c) Deferoxamine can cause allergic reactions (pruritus, wheals,
rash, anaphylaxis)

Front 19

Interrelationships and metabolic roles of vitamin B12 and folic acid

Back 19

Vitamin B12 and folic acid are dietary essentials for man. Deficiency in either of
these substances results in defective synthesis of DNA in any cell attempting
chromosomal repair or division. Tissues with the greatest rate of cell turnover show
the most dramatic changes; the hematopoietic system is especially sensitive.
Interrelationships and metabolic roles of vitamin B12 and folic acid are shown below.
Methyl groups contributed by methyltetrahydrofolate (CH3THF) are used to form
methylcobalamin (CH3B12). Thus without vitamin B12, folate is trapped as CH3THF,
and subsequent steps in folate metabolism that require THF are deprived of
substrate. This provides the common basis for the development of megaloblastic
anemia with deficiency of either vitamin B12 or folic acid.

Front 20

Vitamin B12
A. Biochemistry

Back 20

Two active coenzyme forms of vitamin B12
a. Methylcobalamin (CH3B12), which is important for folate metabolism and
for the formation of methionine and S-adenosylmethionine from
homocysteine
b. Deoxyadenosylcobalamin which is required for the isomerization of
L-methylmalonyl CoA to succinyl CoA.

Front 21

Disposition of vitamin B12

Back 21

1. B12 is released from digested
protein by the actions of gastric
acid and pancreatic enzymes
2. Intrinsic factor, secreted from
parietal cells binds B12
3. The complex interacts with
specific receptors on ileal
mucosal cells, is absorbed and
enters the circulation
4. Once absorbed, B12 binds with
transcobalamin II (TcII) for
transport to tissues
5. The complex is preferentially
distributed to the liver (up to
90%)
6. Most circulating cobalamin is bound to transcobalamin I and III
7. An alternate pathway for absorption exists which does not require intrinsic
factor or an intact terminal ileum. The pathway involves passive diffusion
and accounts for 1% of ingested B12.

Front 22

B12 Deficiency--Causes

Back 22

Deficiency (takes several years to develop following vitamin deprivation du eot
enterohepatic circulation of the vitamin)
1. Causes
a. Intestinal disease or defects that interfere with absorption of intrinsic
factor-B12 complex
b. Inadequate secretion of intrinsic factor (pernicious anemia)
c. Damage to ileal mucosal cells by disease or surgery

Front 23

B12

Effects of deficiency

Back 23

a. Megaloblastic anemia
b. Potentially irreversible nerve damage causing a wide range of
neurological signs and symptoms including parethesias of the hands and
feet, decreased vibration and position senses with resultant
unsteadiness, decreased deep tendon reflexes, and, in later stages,
confusion, moodiness, loss of memory, and loss of central vision

Front 24

B12 Deficiency Diagnosis

Back 24

a. Determination of the plasma concentration of B12
b. Examination of blood smear (macrocytosis and hypersegmented
polymorphonuclear leukocytes)

Front 25

B12 Deficiency--Treatment

Back 25

a. Treatment includes parenteral (IM or SC) cyanocobalamin, especially in
patients with pernicious anemia or ileal disease
b. Oral cyanocobalamin (In patients with pernicious anemia high doses are
used since cobalamin is absorbed via passive diffusion)
c. Nasal spray
d. Evaluating therapeutic outcomes
(1) Patient experiences improved strength and well-being within days
(2) Plasma becomes normoblastic after 7 days
(3) Neuropsychiatric signs and symptoms can be reversible if they are
< 6 months’ duration but 6 months of replacement therapy or longer
may be necessary for improvement. If permanent neurologic
damage has resulted, progression will cease with replacement
therapy.
e. Once begun, therapy is lifelong.

Front 26

Folic acid
A. Biochemistry

Back 26

Pteroylglutamic acid (folic acid) is
reduced to tetrahydrofolic acid
which acts as an acceptor of
one-carbon units

Front 27

Folic acid

Disposition

Back 27

1. Polyglutamates in food are
hydrolyzed, reduced, & then
methylated by dihydrofolate
reductase
2. methyl-THF is transported to
tissues and is taken up by
receptor-mediated endocytosis
3. Methyl-THF acts as a methyl donor (for formation of CH3B12) and as a
source of THF.
4. The liver reduces & methylates folic acid (PteGlu) and transports CH3THF
into the bile for reabsorption by the gut.
5. Folate is stored within cells as polyglutamates.

Front 28

Folic Acid

Deficiency Causes

Back 28

Causes of deficiency (4-5 months for megaloblastosis to develop once
dietary folic acid is stopped)
a. Acute or chronic alcoholism (most common) where daily intake is DECR &
ethanol is toxic to hepatocytes
b. Drugs
(1) Inhibitors of dihydrofolate reductase (methotrexate, trimethoprim)
(2) Drugs which interfere with absorption and storage of folate (certain
anticonvulsants and oral contraceptives)
c. Diseases of small intestine which interfere with absorption of folate &
enterohepatic recycling.

Front 29

Folic acid---Deficiency Effect

Back 29

The principal effect of folic acid deficiency is:
a. Megaloblastic anemia
b. Unlike B12 deficiency, neurological abnormalities are NOT common

Front 30

Folic Acid--Deficiency Dx

Back 30

Diagnosis
a. Determining plasma concentration of folate
b. Examination of blood smear

Front 31

Folic Acid--Treatment

Back 31

a. Therapy is indicated for
(1) Megaloblastic anemia which is treated with IM B12 and folic acid.
(2) Folate also is used for prophylactic administration when there is
increased utilization such as in pregnancy and lactation.
(Folate deficiency during pregnancy is associated with congenital
neural tube defects.)
b. Preparations
(1) Oral and parenteral preparations of folic acid; and
(2) Leucovorin (folinic acid) which circumvents the action of inhibitors
of dihydrofolate reductase and potentiates the cytotoxic effects of 5-
fluorouracil.
c. Evaluating therapeutic outcomes
Megaloblastic erythropoiesis disappears within 48 hours
d. Drug interaction: High doses counteract the effects of antiepileptic drugs.