AGEN HEMATINIK

M. Fadhol Romdhoni
Laboratorium Farmakologi
Fakultas Kedokteran
Universitas Muhammadiyah

Pokok Bahasan

Overview
Besi
Vitamin B12
Asam Folat
Faktor Pertumbuhan Hematopoietik

OVERVIE
W

http://www.theironfiles.co.uk/Sickle-cell/General/SCDBlood

http://www.theironfiles.co.uk/Sickle-cell/General/SCDBlood

Haemoglobin
4 globin + 1 haem.
Haem
consists of a tetrapyrrole
porphyrin ring containing
ferrous (Fe2+) iron.
Each haem group can
carry 1 oxygen molecule
bound reversibly to Fe2+
and to a histidine residue in
the globin chain basis of
oxygen transport.

Anaemia
Definition: [Hb] in blood &/ RBC per age, sex
and geographical location.
Normal Hb:
14g to 16g /dl in Male
13g to 15g /dl in Female
Acute: fatigue chronic: asymptomatic.
Classification based on indices of red cell are:
hypochromic, microcytic anaemia
macrocytic anaemia
normochromic normocytic anaemia
mixed pictures.

BALANCE
INPUT

OUTPU
T

MACHINE

IMBALANCE
<<<< INPUT:
Nutritional
deficiency

BROKEN
MACHINE
- - Synthesis <<
- - Chronic

>>>OUTPU
T:
Bleeding
Haemolysi
s

Causes of Anaemia
Formation
1.Nutritional
Iron Deficiency
Folic Acid/ Vit
B12Deficiency
Protein Deficiency

2.Decreased
Synthesis
Aplastic Anaemia
Replacement of BM (e.g.
Leukaemia)
Thalassaemia

3.Chronic Disorder
Kidney Disease
Advanced Malignancy
Chronic Liver Disease

Destruction
1.Post
Haemorrhage
Acute & chronicBlood Loss

2.Excessive
Haemolysis
Intracellular Defect
(Defective RBC)
Thalassaemia
Haemoglobinopathies
Sickle Cell Anaemia

Extracellular Defect
Rh Incompatibility
Auto Immune Haemolytic
Anaemia
Certain Snake Venom

BESI

Farmakologi dasar
Farmakokinetik
Farmakodinamik
Farmakologi Klinis
Toksisitas Klinis

Farmakologi dasar
Important properties :
several oxidation states
form stable coordination complexes
Fe + protoporfirin Heme
Heme + globin Hemoglobin
Hemoglobin binds O2 & provides O2 delivery
Fe deficiency microcytic hypochromic anemia
Body content of iron:
Essential: myoglobin, Hb, enzym, transferrin not
available for haemoglobin synthesis
Storage: Ferritin, hemosiderin Hb synthesis

P
H
A
R
M
A
C
O
K
I
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T
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S

Pharmacokinetics:
Absorption

Daily diet : 1015 mg absorbption 510%

Location : duodenum and proximal jejunum
Heme iron directly absorbed
Nonheme iron reduced to ferrous (Fe2+)
absorbed
Iron crosses the luminal membrane by active transport of
ferrous iron and absorption of iron complexed with heme
DMT1 transporter
absorbed iron can be actively transported into the blood
by ferroportin and oxidized to ferric iron (Fe 3+)
Excess iron can be stored in intestinal epithelial cells as
ferritin

Pharmacokinetics: Transport
Iron is transported in the plasma bound to
transferrin
Transferrin-iron complex receptor-mediated
endocytosis enters maturing erythroid cells
Endosomes: ferric ferrous transported by
DMT1 hemoglobin synthesis or stored as
ferritin.
The transferrin-transferrin receptor complex is
recycled to the plasma membrane, where the
transferrin dissociates and returns to the plasma.

Pharmacokinetics: Storage
Storage :

in intestinal mucosal cells: as ferritin

in macrophages in the liver, spleen, and
bone, and in parenchymal liver cells.

Apoferritin synthesis is regulated by the

levels of free iron.
Ferritin present in serum is in
equilibrium with storage ferritin in
reticuloendothelial tissues the serum
ferritin level can be used to estimate
total body iron stores.

Pharmacokinetics:
Elimination
no mechanism for excretion
Small amounts are lost in the feces
by :
exfoliation of intestinal mucosal cells
trace amounts are excreted in bile, urine,
and sweat
no more than 1 mg of iron per day.

regulation of iron balance :

absorption and storage

http://izzrawda.wordpress.com/2009/03/16/do-you-have-an

Iron Deficiency Anemia

The daily requirement of iron
Male : 1mg / day
Female
2mg / day
3mg / day (during pregnancy and lactation)
Iron deficiency anaemia can occur under the
following four conditions:
Less Intake of Fe, Vitamins and Protein
Diminished Absorption
Increased Loss
Excessive Demand

Iron: Indication
Basically: Iron deficiency
Application:
Iron deficiency due to dietary lack or to
chronic blood loss.
Pregnancy: TM2
GIT abnormality: malabsorption
Premature baby
Early treatment of pernicious anemia

Preparation
Oral:

ferrous sulfate, ferrous succinate, ferrous

gluconate and ferrous fumarate.
SE: GIT upset, blackened stool, teeth stain
Form: tablet, liquid, sustained-release

Parenteral iron

Indication: not able to absorb oral iron

Prep

Deep IM: iron-dextran (50 mg Fe/mL) or iron-sorbitol

precaution: local reaction, anaphylaxis

Slow IV: iron dextran, sodium ferric gluconate

complex, iron sucrose
Precaution: risk of anaphylacsis!!!

Oral iron should not be given 24 h before i.m. begin

and for 5 days after the last i.v. injection;

 Therapeutic dose:
3-6 mg/Kg/day of elemental ironInduces an Hb
of 0.25-0.4 g/dl per day or 1%/day rise in
hematocrit.

Adequate response:
Hb of 2 g/dl after 3 weeks of tx

Failure of response
after 2 weeks of oral iron requires reevaluation for
ongoing blood losses,infection,poor compliance or
other causes of microcytic anaemia.

Priority: oral preparation.

Interactions
Iron chelates in the gut with tetracyclines,
penicillamine, methyldopa, levodopa,
carbidopa, ciprofloxacin, norfloxacin and
ofloxacin;
it also forms stable complexes with
thyroxine, captopril and biphosphonates.
Ingestion should be separated by 3 hours.
absorption: vit C
absorption: desferrioxamine, tea
(tannins) , Ca, Zn, and bran

Contraindications
chronic infection
in haemolytic anaemias unless there
is also haemoglobinuria
increased erythropoiesis associated with
chronic haemolytic states stimulates
increased iron absorption and adding to
the iron load may cause haemosiderosis.

Unwanted effects of iron

Dose related, include nausea, abdominal cramps and
diarrhoea.
overcome : dose or by taking the tablets after or with meals

Acute iron toxicity

Ingestion of large quantities of iron salts.
Result: severe necrotising gastritis with vomiting,
haemorrhage and diarrhoea collapse
Treatment : gastric lavage with NaHCO3, iron
chelating agent, and treatment of causes.
Chronic iron toxicity
Caused by conditions other than ingestion of iron
salts,
Cause pancreatic damage and leading to diabetes.

Iron Overload

Iron chelators

Iron chelators

Used for treatment of iron toxicity

Desferrioxamine(Desferal) (t1/2 6 h).
not absorbed from the gut but is nonetheless given
intragastrically following acute overdose (to bind iron in the
bowel lumen and prevent its absorption) as well as IM and IV
In severe poisoning: slow IV too fast: hypotension
forms a complex with ferric iron, excreted in the
urine.
Deferiprone
orally absorbed
to treat iron overload in patients with thalassaemia major
careful monitoring : Agranulocytosis and other blood
dsyscrasias

VITAMIN B12
Farmakokinetik
Farmakodinamik
Farmakologi klinis

Vitamin B12: Structure

a porphyrin-like ring
with a central cobalt
(Co) atom attached t
o a nucleotide

Structure of Vit B12

(Therapeutic uses)

Cyanocobalamin

Hydroxocobalamin

Where You Can Get Some Vitamin B12!

Mostly animal
products:

Meat
Fish
Eggs
Milk and Milk
products like yogurt

fortified with
Vitamin B12:
Breakfast Cereals
Bread

Vitamin B12: Introduction

Ultimate source: microbial synthesis

not synthesized by animals /plants.

Must be converted to methyl-B12or ado-B12

Daily diet
= 5-25 g
Daily requirement = 2-3 g.
= extrinsic factor
Role: DNA synthesis

Vitamin B12:
Pharmacodynamic
Conversion of methyl-FH4 to FH4
synthesis DNA

Isomerisation of methylmalonyl-CoA to
succinyl-CoA.

Vitamin B12:
Pharmacodynamic
Methyl-FH4 donates
the methyl group
to B12, the cofactor.
The methyl group
is then transferred
to homocysteine to
form methionine
Deficiency:
methylfolate trap

Synthesis of DNA

Vitamin B12:
Pharmacodynamic
Vit B12 deficiency : acummulation
of methyl malonate-CoA basis of
neuropathy in vit B12 deficiency

Mechanism for Peripheral

Neuropathy
Cobalamin is a cofactor for the enzyme
Methylmalonyl-CoA mutase which converts
methylmalonyl-CoA to succinyl-CoA.
Succinyl-CoA enters the Krebs cycles and
goes into nerves to make myelin.
If no Vitamin B12, methylmalonyl-CoA goes
on to form abnormal fatty acids and
causes subacute degeneration of the
nerves. Only B12 can correct this problem.

Vitamin B12:
Pharmacokinetic
Normal B-12 absorption:
Dietary B-12 binds to R factor in saliva and
gastric juices.
In duodenum, pancreatic enzymes promote
dissociation from R factor and binding to
Intrinsic Factor (IF)
IF-B12 complex taken up by ileal receptor
cubilin.
Released into plasma bound to
transcobalamines TC I, II, or III.
Enters cells through receptor mediated
endocytosis and metabolized into two
coenzymes: adenosyl-Cbl and methyl-Cbl.

Vitamin B12: Pharmacokinetic

Another mechanism for B12 absorption involves
diffusion and not IF : jejunum
In circulation, cobalamin binds to
transcobalamin II; transporting the vitamin from
the enterocyte to the liver and other organs
Biliary excretion of B12 is much higher than
excretion in urine or feces

Vitamin B12:
Absorption& Distribution

Vitamin B12:
Absorption& Distribution
Iiver
disease

Vegetarian
Pernicious
Anemia

Ileal
disease

Vitamin B12: Indication

Pernicious anaemia :deficiency IF
Dietary deficiency: vegetarian
Malabsorption syndromes (>>>) :
stagnant loop syndrome ,Crohns disease, Fish
tape worm infestation, gastrectomy

requirements:
pregnancy, hemolytic anemia, hepatic disease

Vit b12 absorption test

Neurologic syndrome: Vit B12 deficiency

Vitamin B12 : Deficiency

Caused by absorption
intrinsic factor
Interference of absorption in the terminal ileum
e.g. Colon resection in Crohn's disease

Clinical form:
Pernicious anemia
Neurological disease
peripheral neuropathy, Dementia, subacute combined
degeneration of the spinal cord

Abnormalities of epithelial tissue,

e.g. sore tongue andmalabsorption

Vitamin B12 :
Diagnosis of Deficiency
Lab:
serum vit B12 (N: 170-925 nanogram/1)

Blood film:
pancytopenia, anisopoikilocytosis with
oval macrocytes and hypersegmented
neutrophils; the marrow is megaloblastic

Schilling test :
distinguish between gastric and intestinal
causes

Megaloblastic Anemia

Megaloblastic Anemia

Vitamin B12 :
Contraindication & Interaction
Contraindication
Inconclusively diagnosed anaemia
Allergic to cobalt

Interaction
Alcohol, aminosalicylic acid, neomicine
and colchicine may decrease the
absorption of oral vit B12

Vitamin B12: Preparation

Hydroxocobalamin is preferred to cyanocobalamin:
First choice : injection
Initial dose:
hydroxocobalamin 1 mg i.m. every 2-3 days for 5 doses to induce
remission and to replenish stores

Maintanance dose: 1 mg/3 months

Response:

Feel better : 2 days

Reticulocyte peak : 5-7 days
Hb, RBC, Ht : first week normalize: 2 months
Watch: hypokalemia!!

Vitamin B12: Preparation

If injections are refused
rare allergy, bleeding disorder
Alternative: snuff , aerosol , oral
Large daily oral doses (1000 micrograms)
depleted stores must be replaced by parenteral
cobalamin before switching to the oral
preparation;
the patient must be compliant;
monitoring of the blood must be more frequent
adequate serum vitamin B12 levels must be
demonstrated.

Vitamin B12: Preparation

Synthetic vitamin B12
Cyanocobalamin, hydroxocobalamin
Oral cyanocobalamin : well absorbed, highly protein
bound to the transcobalamins
Metabolize in the liver, followed by biliary and urinary
excretion
T1/2 is about 6 days
Cyanocobalamin injection containing benzyl alcohol :
should not be used for neonates or immature infants

Vitamin B12: interaction

Reduction of absorption of B12 from GI tract
excessive consumption of ethanol for
longer than 2 weeks
prolonged use of cholestyramine, colchicine
large doses of ascorbic acid may destroy
B12

Vitamin B12: Adverse Effect

Usually do not occur
when a megaloblastic anaemia due
to pernicious anaemia is incorrectly
diagnosed as due to folate
deficiency; here folic acid, if used
alone (see below) may accelerate
progressionof subacute combined
degeneration of the nervous system.

ASAM FOLAT
Farmakokinetik
Farmakodinamik
Farmakologi Klinis

Folic Acid
composed of a
heterocycle, paminobenzoic acid,
and glutamic acid

Folate: Pharmacodynamics

Folate:Pharmacokinetics
Human requirement :
varies from 25-35 mcg/d in infancy to up to 100
mcg/d in adults

Total body folic acid stores :

5-10 mg, half of which is stored in the liver as N-5methyltetrahydrofolate

> 2% is degraded daily

so a continuous dietary is essential

Folate:Pharmacokinetics
Active absorption : mainly in the proximal part
of the small intestine
Conjugate in the epithelial cells converts the
polyglutamates into absorbable
monoglutamates
Pharmaceutical product : completely absorbed
in the upper duodenum, even in the presence
of malabsorption
Excretion: entirely as metabolites by the kidney

Folate:Pharmacokinetics

Folate: Pharmacokinetics

Inadequate
dietary supply

Uremia
alcoholism,
hepatic disease

Small
intestinal
disease
Vitamin B12
deficiency

Folic acid deficiency anemia

Etiology :
Most causes : inadequate diet, alcoholism,
pregnancy, malabsorption syndrome
Other causes : increased requirement, enhanced
metabolism, interference in the metabolism

Several reasons for folate def. in alcoholics

reduced dietary intakes, inactivation of folate
conjugate, impaired enterohepatic cycling, depletion
of liver folate stores

Folate Deficiency
More often malnourished than those
with cobalamin deficiency
Gastrointestinal manifestations
More widespread and more severe than
those of pernicious anemia
Diarrhea is often present
Cheilosis
Glossitis

Neurologic abnormalities do not occur

Stages of folate deficiency

1. Negative folate balance (decreased
serum folate)
2. Decreased RBC folate levels and
hypersegmented neutrophils
3. Macroovalocytes, increased MCV,
and decreased hemoglobin

Diagnosis of folate deficiency

Diagnosis :
Megaloblastosis
possibly due to folic acid deficiency must be interpreted in the
light of B12 status
Peripheral blood and bone marrow biopsy look exactly like B12
deficiency

Reduced folate tissue levels :

erythrocyte folate concentration<140 ng/ml
more reliable of tissue stores
Plasma folate level : <3 ng/mlfluctuates
Only increased serum homocysteine levels but NOT serum
methylmalonic acid levels

Folic acid deficiency anemia

Management :
Folic acid should not be given until B12 def. and
pernicious anemia have been excluded
Oral dose: 1 mg/day
Absorption is normal : 50-100 mcg/d
Malabsorption : 250-500 mcg/d
To replenish depleted folate stores, a daily dose of 1-2
mg/d for 2-3 weeks
Duration of therapy depend on underlying causes : 3-4
months to clear folate-deficient erythrocytes from the
blood

Folic acid deficiency anemia

Prophylactic folate therapy :
pregnancy, particularly in women with poor diets,
multiple pregnancies, or thalassemia minor : 300
mcg/d in the last trimester

Monitoring :
Reticulocyte count : peaks 5-8 days after
treatment
Increase Hct
Decrease to normal MCV

Inappropriate Treatment of Pernicious

Anemia With Folate

Vitamin B12 deficiency anemia can be temporarily

corrected by folate supplementation

However, this does not correct the neurologic deficits

Folate draws vitamin B12 away from neurologic

system for RBC production and can exacerbate
combined systems degeneration

Therapeutic Uses of Folic Acid

Megaloblastic Anemia
due to inadequate dietary intake of folic acid
due to chronic alcoholism, pregnancy, infancy,
impaired utilization: uremia, cancer or hepatic
disease.

Anemia associated with dihydrofolate reductase

inhibitors.
i.e. Methotrexate (Cancer chemotherapy),
Pyrimethamine (Antimalarial)

Administration of citrovorum factor

(methylated folic acid) alleviates the anemia.

Therapeutic Uses of Folic Acid

(cont)
Ingestion of drugs that interfere with intestinal
absorption and storage of folic acid.
Mechanism- inhibition of the conjugases that break off
folic acid from its food chelators.
Ex. phenytoin, progestin/estrogens (oral
contraceptives)

Malabsorption Sprue, Celiac disease, partial

gastrectomy.
Rheumatoid arthritis increased folic acid
demand or utilization.

Treatment of folate
deficiency
Oral replacement therapy
Folate prophylaxis
Women planning pregnancy are advised to take 400 g
folic acid daily before conception and until 12 weeks of
pregnancy to prevent neural-tube defects (5 mg/day for
women with a previous affected pregnancy)
Folate fortification of cereal grains at 14 mg/kg has
been made mandatory in the USA as an additional
method of improving the folate status of the population.
Prophylactic folate is also recommended in other states
of increased demand such as long-term hemodialysis
and chronic haemolytic disorders

Foods With Folic Acid

Dark green leafy
vegetables, like
spinach
Broccoli,
asparagus, green
peas and okra
Orange juice
BePapaya
sure to eat 5 servings of
fruits & vegetables such as
these every day!

Beans, lentils
and black-eyed
peas
Soybeans and
tofu
Peanut butter
Fortified foods:
Cereal, rice,
pasta, tortillas,
grits

 Drugs implicated in causing :

* malabsorption ?
* impaired metabolism
- phenytoin
- methotrexate
- barbiturates
- pyrimethamine
- sulfasalazine
- trimethoprim
- cholestyramine
- pentamidine
- oral contraceptives

Barriers to Folic Acid

Absorption or Use
Alcohol
Tobacco
Aspirin, ibuprofen,
naprosyn and
acetaminophen
Antacids & antiulcer medications

Source: Folicacid.net.

Some antiseizure
medications
Some anticancer
drugs
Some antibiotics/
antibacterials
Oral hypoglycemic
agents

TUGAS BACA !!!

FAKTOR PERTUMBUHAN
HEMATOPOIETIK
Eritropoietin
Faktor pertumbuhan mieloid
Faktor pertumbuhan megakariosit

REFERENCES
Basic and Clinical Pharmacology 11th Ed,
Katzung
Pharmacology Rang et al 5th Edition
Goodman & Gilmans The Pharmacological
Basis of Therapeutics, 11th ed.
Color atlas of pharmacology
Clinical Pharmacology, 9th Ed
USMLE Pharmacology Recall
Pharmacology for the health care profession

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