st

Pharmacology 3.2 1 Sem/A.Y. 2015-2016

Hematinics, Hemostatics and Coagulants
Glenn V. Guevara, MD September 11, 2015

OUTLINE B. Erythropoiesis
A. Introduction
B. Anemia
C. Iron Deficiency Anemia
D. Hypoproliferative Anemia
E. Megaloblastic Anemia
F. Myelopoiesis
G. Megakaryopoiesis
H. Hemostasis
I. Summary

HEMATINICS, HEMOSTATICS AND COAGULANTS

A. INTRODUCTION
A. Hematopoiesis Figure 2: Erythropoiesis

 Erythropoietin: main regulator of erythropoiesis

o Stimulate hematopoietic stem cells from the bone
marrow to form RBCs
o Released by kidneys in response to low O2 tension
o Factors that decrease tissue oxygenation: low blood
pressure, anemia, low hemoglobin, poor blood flow,
pulmonary disease
o Increased number of RBCs results to an increased O2
carrying capacity, inducing a negative feedback on
EPO

Figure 3: Erythropoietin stimulation and inhibition

 Iron: needed for maturation of red blood cells

Figure 1: Hematopoiesis o Each RBC contains several hundred hemoglobin
molecules which transport oxygen
o Iron is needed for the production of heme
 Formation of blood components
 Cobalamin
o Erythropoiesis: formation of RBCs
o Myelopoiesis: formation of granulocytes and  Folic Acid
monocytes
o Megakaryopoiesis: formation of platelets B. ANEMIA
 Derived from hematopoietic stem cells  Decrease in the amount of RBCs or hemoglobin in the
blood
 Leads to lowered ability of blood to carry oxygen

Causes:
o Blood loss (most common cause): trauma, GI
bleeding, abnormal menstrual bleeding
o Decreased RBC production
 Nutrient deficiency (iron, cobalamin, folic acid);
most common cause among decreased RBC
production

2018-A DOMONDON, DUENAS, D UNGO, ENCARNACION, ENRIQUEZ 1OF13

Pharmacology 3.02
 Thalessemia
 Bone marrow cancers Hematocrit (Hct)
 Kidney disease
 Chronic infections Male 45 %
 Fluid overload- decrease in RBC production due to Female 40 %
volume expansion Hgb Count
 Increased RBC breakdown- Sickle Cell Disease
Male 13.8 to 18.0 g/dl (8.56-11.17
Types of Anemia mmol/L)
o By size: normocytic, macrocytic, microcytic Female 12.1 to 15.1 g/dl (7.51-9.37 mmol/L)
o By color: normochromic, hypochromic, hyperchromic Children 11-16 g/dL (6.83-9.93 mmol/L)
Pregnant 11-14 g/dL (6.83-9.93 mmol/L)
RBC Count
Signs and Symptoms
Male 4.7-6.1 millions/uL
Female 4.2-5.4 millions/uL
MCV 80-100 fl (femtoliters)
MCH 27-31 pg/cell (picograms)
MCHC 32-36 g/dL or 19.9-22.3 mmol/L
Table 1: Normal values for CBC

C. IRON DEFICIENCY ANEMIA

 Most common cause of anemia
 Due to increased iron demand, iron loss or decreased
iron intake
 More common in females (so take care and love your mom, sisters,
daughters and girlfriends, boys.  There are a lot of illnesses associated
with women.)
 Microcytic and hypochromic

Causes:
 Increased demand
o Growth and development – children, adolescents
o Pregnancy
Figure 4: Shows a somewhat good looking man with a
creepy gaze. Also shown are the General Signs and  Blood loss
Symptoms of Anemia. o Parasitic infections
o Menorrhagia
Diagnostic Tests o Peptic ulcers
o Hemoglobin Count – hemoglobin concentration o Patients on anticoagulants (aspirin, clopidogrel, etc)
o Hematocrit - proportion of blood volume occupied by
RBC; also called "packed cell volume" or "erythrocyte  Decreased intake
volume fraction" (about 3x the Hgb concentration) o Low iron diet: vegetarians, vegans 
o RBC Count – number of RBC o Malabsorption: intestinal resection, celiac disease,
o Mean Corpuscular Volume (MCV) inflammatory bowel disease, decreased acidity of
 Average volume or size of RBC stomach (due to prolonged proton pump inhibitor use,
 MCV = (Hct x 10) / RBC number in million e.g. omeprazole)
 Normal MCV and decreased Hgb/Hct =
normocytic anemia; low MCV = microcytic and A. Diagnostic Tests
(Why do we need to know this? Kinda boring but just see yourself as House,
vice versa Shepherd, Yang or Grey diagnosing your anemia patient. Wee!)
o Mean Corpuscular Hemoglobin (MCH)
 Average mass of hemoglobin per RBC in a CBC (see diagnostic tests of anemia)
sample of blood
 Assess COLOR of the ANEMIA Serum iron
 MCH = (Hgb x 10) / RBC number in million  It is the amount of circulating iron bound to transferrin
o Mean Corpuscular Hemoglobin Concentration  It can increase immediately on initiation of Fe
(MCHC) supplementation
 Concentration of hemoglobin in a volume of packed
RBC – the HUE OF RBC Serum ferritin
 MCHC = MCH/MCV x 100  Most SENSITIVE indicator but is not reliable if within
 This is more sensitive for measuring the actual
normal limits
color because it considers both MCV and MCH
 Remember that ferritin is the storage form of iron
o Blood Smear – morphology of RBCs

2018-A DOMONDON, DUENAS, D UNGO, ENCARNACION, ENRIQUEZ 2OF13

 Pharmacology 3.02
Total Iron Binding Capacity (TIBC)
 Most SPECIFIC indicator (when levels are high)
 It measures the blood capacity to bind iron with
transferrin. It is an indirect measure of transferrin
 Transferrin is the transporter of iron in the blood. An
increase would point to an increased need for iron
(2017B)
 It is usually elevated in IDA

Transferrin Saturation Index (Percent Saturation/ Iron

Saturation)
 It is the percent saturation or iron saturation of
transferrin
 How much iron is currently bound to transferrin
(2017B)
 SI/TIBC x100

Table 2: Normal values

Serum Iron
Male 65-176 μg/dL
Female 50-170 μg/dL
Children 50-120 μg/dL
Figure 5: Increasing severity of iron imbalance up to Iron
Newborn 100-250 μg/dL
Deficiency Anemia. Note the boxes in green, which indicate
Serum Ferritin which stage would the first time the lab findings will appear
Male 18-270 ng/mL (2017B). As the disease progresses, the other parameters that
Female 18-160 ng/mL were normal become lower.
Children 7-140 ng/mL  With a Negative Iron Balance, bone marrow iron stores,
Newborn 25-200 ng/mL serum ferritin decrease while TIBC increases.
Total Iron Binding Capacity 240-450 μg/dL  With Iron Deficient Erythropoiesis, also SI, % saturation,
Transferrin Saturation Index marrow sideroblasts decrease while RBC
Male >15-50%
protoporphyrin increases.
Female >12-50%
 With IDA (which is severe), there is also morphological
Still Possible 5-10%
change in the RBC
Definitely Abnormal <5%

Table 3: Differentiating microcytic anemia causes via lab

tests. These are the different diseases that can present with
microcytic anemia but focus your attention on IDA. There’s a
lower serum iron, % saturation, and serum ferritin but a higher
TIBC. If you order for a smear in IDA patients, you’d see a
microcytic & hypochromic morphology.

Tests Iron Inflammation Thalassemia Sideroblastic

Deficiency
Smear Micro/hypo N/micro/hypo Micro/hypo w/ Variable
targeting
Serum Iron <30 <50 (N) to high (N) to high
TIBC >360 <300 (N) (N)
%saturation <10 10-20 (N) 30-80 30-80
Ferritin <15 30-200 (N) 50-300 50-300
Hemoglobin (N) (N) Abnormal (N)

Figure 6: Hemoglobin Synthesis. Protoporphyrin IX is the

step before heme. When it binds to iron, then there is the
formation of heme. If there is an increase in protoporphyrin if
there is no iron available in circulation. Thus no heme is formed.
In severe forms of iron deficiency anemia, you see a lot of
immature RBC in the blood. Thus, you’ll need iron
supplementation to normal it out.

2018-A DOMONDON, DUENAS, D UNGO, ENCARNACION, ENRIQUEZ 3OF13

Pharmacology 3.02
B. Iron  Ferrous fumarate- usually combined with
 In 1 mL of RBC, you will get 1 mg iron multivitamins like folic acid and Vit-B complex
 Daily need: 15-20 mg/day (of elemental iron) due to 10-  To reverse the anemia
15% absorption of dietary iron o You need to give iron supplementation for 3-
o M: 1 mg/day 12 months.
o F: 1.5 mg/day o In Harrisons, they suggested giving
o Higher requirement for: 300mg/day elemental iron but according to
 Pregnant: 2-3x (5-6 mg) WHO, you can start with 60 mg/day elemental
 Children/adolescents: 1.5x iron for patients with mild-moderate anemia.
 Vegetarian diet has 50% less iron absorption o Eg. If a patient needs 60mg/day of elemental
 High in Fe: iron, you can give ferrous sulphate hydrated
o red meat which has 65 mg. If you have a patient who
o egg yolk needs 300mg/day of elemental iron, then you
o dark leafy greens (spinach) need to give 5 tablets of ferrous sulphate
o dried fruit (raisins, prunes) hydrated.
o iron enriched foods (cereals, grains)
o mollusks (clams, oysters) Benefits of Effective Iron Supplementation Programs
o beans (soybeans) (Mentioned last year. From 2017 B)
 Children/adolescents
Different forms of Iron: o improved behavioral and cognitive development
 Heme iron o improve child survival
o Red meat (Eww. Eat white meat to be healthy.)  Pregnant women and their infants:
o absorbed directly through the heme transporter o decreased incidence of low birth weight babies
 FerrIc: IV supplement (e.g. Ferric Dextran) and perinatal mortality
o Why is it given parenterally? o decreased maternal mortality/obstetrical
This is because it must be first converted to complications
ferrous by duodenal cytochrome B (a  All individuals
ferrireductase) to be absorbed in GIT. o improved fitness and work capacity
 FerrOus: Oral preparations (e.g. Ferrous gluconate) o improved cognition
o Why oral? Because it can be directly absorbed by
the intestinal cell via DMT 1 Table 4: Common Oral Iron Preparations
Remember: Fair (Fer) ROD and RICky B
ROD: FerRous, Oral, Direct, DMT 1 Generic Name Percent Tablet Elixir Properties
RICky B: FerRiC, IV, duodenal cytochrome B Elemen (5 ml)
tal Iron
Storage and Transport (Mentioned last year. From 2017 B) Ferrous 20 % 325 300 Commonly
 Inside the intestinal cell, iron is stored as ferritin. sulphate (65) (60) given due to
 If iron is needed, it moves out as ferrous, becomes hydrated tolerability,
converted to ferric, and ferric binds to transferrin -> (dehydrate effectiveness
circulates in blood tetrahydrate) and low cost
Katzung: Ferritin is a B-globulin that can bind 2 molecules of More of the GI
ferric iron. irritation effect
195 90
C. Management (39) (18)
 Packed RBC Transfusion – for SEVERE ACUTE ANEMIA
o Usually secondary to blood loss Ferrous 30-32%
o Supplementation can be started as adjunct but onset of sulphate
effects will be delayed dessicated
 Oral iron (monohydrate)
 Parenteral iron With incipients
Extended 20% 525 to prolong
D. Oral Iron Preparations (Refer to Table 4) Release (105) release
 What you need to memorize in the table is the ferrous sulfate
elemental iron.
Ferrous 33 % 325 H% elemental
 Remember that the supplement is often iron + a base
fumarate (107) iron; same
salt (sulfate, fumarate). Sometimes they don’t show the
elemental Fe in parenthesis and you have to compute effectiveness as
from the dosage. (2017B) sulfate
 Elixirs are available for children and for patients who
cannot swallow. 195 100
 Ferrous gluconate- given to children with iron (64) (33)
deficiency anemia. It is usually prepared as an elixir Ferrous 20% 75 (15) Iron amino acid
and combined with multivitamins. bisglycinate chelate; good
 Extended release has excipients to prolong release absorption &
(2017B) high

2018-A DOMONDON, DUENAS, D UNGO, ENCARNACION, ENRIQUEZ 4OF13

Pharmacology 3.02

bioavailability G. Response to Treatment

 Reticulocyte count increases in 4-7 days after initiation of

Ferrous 12% 325 300 Similar efficacy
gluconate (39) (35) and tolerability
as that
sulfate
Polysaccharide 100% 150 100 Ferric complex
iron (eg. (150) (100) with hydrolysed
Maltose iron) starch; less GI
irritability;
E. WHO Guidelines of Iron Supplementation (from lecturer’s
lecture slides)
 The goal is to reverse anemia and provide 1g iron
stores for up to 3-12 months.
 Patients under iron supplementation have to be
evaluated every month (2017)
 Dosage: 60mg-300mg/day (300 is what Harrisons
recommends but for mild to moderate anemia, start at
60 mg)
 Adults: 60 mg
 Pregnant: 60 mg iron/400 μg folic acid for 6 months of
pregnancy but may extend 3-6 months postpartum
o Start supplementation at the SECOND
trimester (2017)
st
o Higher toxicity in 1 trimester (2017)
o Metallic taste exacerbates vomiting in the
st
mother in 1 trimester (2017)
 Child 6-24 months: 12.5 mg iron/50 μg folic acid
(N 6-12 months; LBW <2500g 2-24 months)
 Child 2-5 yrs: 20-30mg iron
 Child 6-11 yrs: 30-60 mg
 Adolescents and adults: 60 mg
 Severe anemia
o Child <2 yrs: 25 mg iron + 100-400 μg folic
acid x 3 months
o Child 2-12: 60 mg iron+ 400 μg folic acid x 3
months
o Adolescents, adults, pregnant women: 120
mg iron+ 400 μg folic acid x 3 months
F. Adverse Reactions & Precautions of Oral Iron
 Oral iron may cause GIT distress in 15-20% of patients
o Most common complaint which can decrease compliance
since treatment lasts for months
o Abdominal pain, nausea, vomiting, constipation
o You may switch to delayed release iron supplements
because they have less GIT adverse reactions
o This is often dose-related, another rationale to start low
(Katzung)
 Black stools are a side effect of oral iron. It has no
significant clinical effect except possible masking of
gastrointestinal bleeding in fecalysis. (Katzung)
therapy and peaks at 1 ½ weeks
 After 4 weeks of treatment, you need to see a Hemoglobin
of levels > 20g/dL. Thus first follow up is after 1 month.
 Absence of response may be due to poor absorption,
noncompliance to medication, or confounding diagnosis
 Iron tolerance test –this is for adverse reactions and the
response of a patient
o Give 2 iron tablets on an empty stomach
o Serum iron in 2 hours: If increase is at least 100 μg/dL,
your treatment is adequate.
H. Parenteral Iron Therapy
Indicated for:
 Poor tolerance to oral iron
 Acute condition (blood loss) AS ADJUNCT to packed RBC
transfusion
 Most common use: Large demand for iron from patients
being treated with erythropoietin (which cannot be
satisfied by oral iron) especially hemodialysis patients or
patients with kidney problems
Calculate the daily dose as follows:
 Body Weight (kg) x 2.3 x (15 – px Hgb in g/dL) + 500 or
1000 mg (depending on target iron stores)
Two ways to administer
 Administer total dose of iron required to correct deficit and
provide at least 500 mg iron stores (can lead to more ADRs)
 Give repeated small doses for certain period of time (most
commonly used by doctors)
Forms of parenteral iron
 Iron dextran
o Contains 50 mg/mL elemental iron
o Not being used anymore high risk of anaphylaxis
o Given <500mg IV/IM (half-life 6 hrs)
 Sodium Ferric Gluconate, Iron Sucrose, Ferumoxytol –
newer drugs
o Given in chronic renal failure (CRF)
o IV ONLY (Katzung)
o Ferritin levels between 500 and 1200 mg/mL and
transferrin saturations of <25%
o Lower risk of anaphylaxis
Precautions (Katzung) (2017B)
 Monitor iron storage levels via SI or TIBC.
 Be careful in giving parenteral iron because overdose and
toxicity can occur more easily as compared to the oral form.
o So, it is important to properly calculate the daily dose
needed by the patient.
I. Iron Toxicity

 Taking the following with oral iron can DECREASE Acute

absorption:
o milk, caffeine, antacids, calcium supplements
 Vitamin C can INCREASE absorption. If you really need to
reverse anemia immediately, then you can give your iron
supplements with Vit C.
 Exclusively in young children who swallow 10 tablets or
more
 Effects include necrotizing gastroenteritis, vomiting,
abdominal pain, bloody diarrhea, shock, lethargy, dyspnea,
coma and death
 Treatment includes:
o Whole bowel irrigation
o Deferoxamine (iron chelating compound)
o Supportive therapy
o According to Katzung, it is useless to give activated
charcoal because it does not bind iron.

2018-A DOMONDON, DUENAS, D UNGO, ENCARNACION, ENRIQUEZ 5OF13

Pharmacology 3.02
 Involved in erythropoiesis; stimulates progenitor
Chronic proliferation and maturation
 Seen in patients given iron for a prolonged period of time at  Involved in wound healing; it stimulates angiogenesis
maximum dose and smooth muscle fiber proliferation
 Usually there is hemochromatosis aka iron overload results  Involved in the brain’s response to neuronal injury
when there is excess iron deposition in heart, liver, pancreas  Involved in vasocontriction-dependent hypertension
etc  Increases iron absorption by suppressing hepicidin
 May be inherited or acquired (mostly acquired)
o Inherited hemochromatosis C. Recombinant Human Erythropoietin
o B-thalassemia leading to repeated RBC transfusions
(Katzung) Epoietin alfa or Darbopoietin alfa
 Treatment includes the ff:  Increase Hct by 4 points and Hgb by 1g/dL in 2 weeks
o Intermittent phlebotomy (removes blood and therefore  Darbopoietin alfa has a half-life 3-4x longer than that of
excess iron; 1 unit/week) epoietin alfa; it is a second generation erythropoiesis-
o Deferasirox: an oral iron chelator stimulating agent
 According to Katzung, phlebotomy is what is usually done  Adverse effects known include, but are not limited to,
because iron chelators are more complicated, expensive, allergic reactions, hypertension, migratory
and hazardous. thrombophlebitis, microvascular thrombosis, pulmonary
o It is only used as a last resort if a phlebotomy is not embolism, thrombosis of retinal artery, temporal veins,
enough. renal veins, headache, tachycardia, edema, shortness of
breath, GI upset (nausea, vomiting, diarrhea), stinging
D. HYPOPROLIFERATIVE ANEMIA sensation at injection site, flu-like symptoms
 In light of this, iron supplementation and anticoagulants
 At least 75% of all cases of anemia are hypoproliferative in may be needed
nature
Dosage for epoietin alfa (Guevarra, 2014):
A. Types and Diagnoses o CRF: 50-150U/kg 3x/week IV or 80-120U/kg 1-3x/week
IV /SQ (Hgb 10-12g/dL 4-6weeks; Hct 33-36% 2-4
Table 5: Diagnosis of Hypoproliferative Anemia months) ; maintained at 300U/kg
o AIDS: 100-300U/kg 3x/week IV/SQ
o Cancer: 150U/kg 3x/week; can reached 450-600U/kg
1x/week
o Surgery: 150-300U/kg OD for 10 days, day of surgery
and 4 days after surgery

Dosage for darbopoietin alfa (Guevarra, 2014):

o CRF: 45µg/kg 1x/wk IV/SQ
o Carries an increased risk of cancer recurrence.

E. MEGALOBLASTIC ANEMIA
 Disorders characterized by presence of macrocytic red
cells in bone marrow
 Causes:
O Cobalamin/folate deficiency
O Abnormality (genetic/acquired) in cobalamin/folate
Iron Deficiency anemia metabolism
 Most common type O DNA synthesis defects

Anemia of chronic disease Cobalamin

 Caused by chronic inflammation (rheumatoid arthritis), TB,  A water soluble vitamin containing a cobalt molecule
tissue injury, and cancer  Plays a role in regulating normal function of CNS, blood
formation, DNA synthesis, DNA regulation
Anemia of renal disease  Synthesized by microorganisms mainly
 Anemia results due to inadequacy of erythropoietin  Coenzymes are methylcobalamin, a coenzyme involved
production secondary to impaired renal function in methionine, S-adenosylmethionine, and tetrahyrofolate
 Examples are chronic renal failure (CRF), uremia, PCKD production, and adenosylcobalamin
 Obtained via intake of fish, meat, dairy products
Anemia of metabolic disease  We obtain 5-30 µg via diet, we lose 1-3 µg per day, a store
 Hypothyroidism and starvation of 2-3 mg is good for 4 years
 Passively absorbed in the buccal area, duodenum, and
*Usual observation is that red cells are normocytic and ileum; actively absorbed in the ileum in the presence of
normochromic gastric intrinsic factor
 Normal range is 150-600 pmol or 200-900 pg/ml
B. Endogenous erythropoietin
 Produced in the kidney by intestinal fibroblasts; hypoxia Cobalamin deficiency can be caused by (Guevarra, 2014):
stimulates its synthesis O Pernicious anemia due to IF loss secondary to
atrophic gastritis

2018-A DOMONDON, DUENAS, D UNGO, ENCARNACION, ENRIQUEZ 6OF13

Pharmacology 3.02
O Inadequate amount of intake
O Gastric and/or ileal resection
O Decrease in gastric acid amount via proton pump
inhibitors and/or H2 blockers
O Alcoholism
O Metformin intake
O Malnutrition
Cobalamin deficiency results to (Guevarra, 2014):
O Topic in question, megaloblastic anemia
O Progressive swelling of myelinated neurons
O Demyelination
O Neuronal cell death; these are seen in the spinal
column and cerebral cortex
O Hand and foot paresthesia
O Decrease in vibration and position sense, with
associated unsteadiness
O Decrease in deep tendon reflexes
O Confusion, moodiness, loss of memory
O Loss of central vision
Vitamin B12 therapy (Guevarra, 2014)
O Given in cyanocobalamin and/or hydroxocobalamin,
as these are the active medicinal forms
O If there is inadequate intake, give orally; if there is IF
deficiency and/or gastric and ileal problems, give
parenterally
O Cyanocobalamin is the first choice: give drug IM /
SQ (not IV as there is a risk of anaphylaxis; skin test
needed), 1-1000µg 1-3x / week; supplementation is
80µg mixed w/ IF (not reliable; e.g. vegetarians)
O An alternative is hydroxocobalamin, given 100 µg
IM; this has a more sustained effect, lasting 3 months
O Treatment usually lasts for 6-12 months, as a long
term treatment; cyanocobalamin is given monthly in
the form of 100 µg injections
O Also given for cases of neuropathies such as
trigeminal neuralgia and multiple sclerosis, psychiatric
disorders, poor growth and/or nutrition, as a tonic for
patients suffering from tiredness and/or easy fatigue
Folic acid
 Vitamin that is obtained from fresh green vegetables, fruits,
liver, and yeast; 90% of vitamin is destroyed in the heat of
cooking
 Normally we obtain 50-500 µg of it per day; vegetarians
only obtain roughly 2 mg/day
 We usually require 400 µg per day; pregnant women
require 500-600 µg per day; they must have an intake of at
least 400 µg per day to prevent defects in the neural tube
 Absorbed in duodenum and proximal jejunum (proximal
small intestine), transported while bound to a plasma-
binding protein
 Normal range is 9-45 nmol or 4-20 ng/mL
Deficiency (Guevarra, 2014)
O Causes are alcoholism, diseases of the proximal small
intestine, inhibitors of dihydrofolate reductase such as
methotrexate and trimethoprim, drugs that interfere
in folate storage in tissues such as oral
contraceptives
O Deficiency of folic acid can result to higher incidences
of defects in the neural tube (anencephaly,
encephaloceles, spina bifida), the topic in question
(megaloblastic anemia), coronary artery and
peripheral vascular diseases, venous thrombosis or
hyperhomocysteinemia
2018-A DOMONDON, DUENAS, D UNGO, ENCARNACION, ENRIQUEZ
Therapy (Guevarra, 2014):
O Given as folic acid, orally or parenterally or part of
MV prep
O Given as a prophylaxis in pregnant women, (dose
of 400-500 µg per day); for hemolytic anemia it is
given at a dose of 1 mg per day
O Can be given as folinic acid (leucovorin calcium), a
derivative of tetrahydrofolate
O Folinic acid circumvents DHF reductase inhibition (ex.
Resulting from methotrexate intake); it is an antidote
for folate antagonist toxicity (ex. Resulting from
trimethoprim and pyrimethamine intake)
O Has no advantage over folic acid; it is actually more
expensive
O Avoid multivitamin preparations; do multivitamin
preparations only if there is evidence of vitamin
deficiency
O Folic acid is well tolerated by the body, even at doses
as high as 15 mg per day
O Folic acid can decrease, even counteract effects of
drugs like phenobarbital, phenytoin, primidone
F. MYELOPOIESIS
 Myeloid growth factors are glycoproteins that stimulate the
proliferation and differentiation of one or more myeloid cell
lines
 Enhance the function of mature granulocytes and
monocytes

 Produced naturally by a number of different cells, including
fibroblasts, endothelial cells, macrophages, and T cells

 GM-CSF is capable of stimulating the proliferation,
differentiation, and function of a number of the myeloid cell
lineages

 G-CSF is restricted to neutrophils and their progenitors,
stimulating their proliferation, differentiation, and function
A. Conditions that affect Myelopoiesis
 Autologous bone marrow transplantation

 Intensive myelosuppressive cancer chemotheraphy
 Zidovudine induced neutropenia in AIDS patients

 Severe congenital neutropenia
B. Recombinant GM-CSF (Sargramostim)
 Produced by yeast 

2
 125-500μg/m /d SQ (Half-life: 2-3hrs) [Katzung says: Serum
T1/2 of 2-7 hours after IV or SQ administration
 Slow infusion: 3-6 hours 

 Lower doses mainly affects neutrophils; larger doses
affect monocytes/eosinophils 

 Adverse Effects: bone pain, malaise, flu-like symptoms,
fever, diarrhea, dyspnea and rash, transient
supraventricular arrhythmia, elevation of serum creatinine,
bilirubin and hepatic enzymes 

7OF13
Pharmacology 3.02
C. Recombinant G-CSF (Filgrastim/Pegfilgrastim) H. HEMOSTASIS

 Filgrastim A. Elements of Hemostasis

o produced by Escherichia coli
  Primary Hemostasis
o Stimulates CFU-G to increase neutrophil o Affected by: aspirin and NSAIDs
production; stimulation of CFU-G to increase o Adequate vascular response, platelets, levels of Von
neutrophil production 
 Willebrand factor
o 1-20μg/kg/d IV infusion for 30 mins 

o Patient on cancer chemotherapy: 5μg/kg/d; daily  Secondary Hemostasis
administration for 14-21 days 
 o Affected by: warfarin and heparin
o Involve the extrinsic factors
 Pelfigrastim o Adequate level of clotting factors, vitamin K
o gene through conjugation of a 20,000-Da
B. Bleeding Disorders

polyethylene glycol moiety to the G-CSF
glycoprotein produced by E. coli  Causes
o Inherited coagulation disorders
o Longer half-life
 clotting factor deficiency
o 6mg SQ
 hemophilia
o Hemorrhagic diathesis of liver disease
G. MEGAKARYOPOIESIS o surgical procedures / multi-organ injuries
 Thrombopoietin, a cytokine that predominantly stimulates o vitamin K deficiency
megakaryopoiesis. It is produced by the liver, marrow
stromal cells, and many other organs. It is the primary C. Diagnostic Tests
regulator of platelet production.  platelet count: 150,000-400,000/m2 

 Interleukin-11 (IL-11) was cloned based on its activity to  bleeding time (measure platelet function): 1-9 mins 

promote proliferation of an IL-6-dependent myeloma cell line  prothrombin time (measure extrinsic pathway; used for
Stimulates hematopoiesis, intestinal epithelial cell growth, 
 warfarin): 11-13.5 sec 

and osteoclasto-genesis and inhibits adipogenesis。  partial thromboplastin time (measure intrinsic pathway;
Enhances megakaryocyte maturation in-vitro; in-vivo used for heparin): 25-35sec
increases peripheral blood platelet counts 

D. Vitamin K
Recombinant Interleukin-11 (Oprelvekin)  cause of bleeding disorder
 fat soluble
 needed for complete synthesis of certain proteins that are
o Bacterially derived 19,000-Da polypeptide 


 required for blood coagulation (II, VII, IX, X) - 1972

 also used to manipulate binding of calcium in bone and
o 25-50 μg/kg/d SQ; Half-life: 7 hours 
 other tissues 


o Administered daily; response in 5-9 days 
 RDI

 Infants: 10–20μg/day

o Used for chemotherapy induced thrombocytopenia  Children & adolescents: 15–100μg/day
in non-myeloid malignancies (20,000/μL). Aim:  Males: 120 μg/day

platelet count reaches 100,000/μL 
  Females: 90 μg/day (lower than males)

o Adverse Effects: Fluid retention and associated Vitamin K Deficiency

cardiac symptoms, such as tachycardia palpitation, o Uncommon 

edema, shortness of breath, blurred vision, injection o Causes: 

site rash or erythema, and paresthesias. 
  Resection of SI

 Malabsorption syndrome

Recombinant Thrombopoietin  Prolonged use of broad spectrum antibiotics
 Diet low in vit. K

o Recombinant Human Megakaryocyte Growth and  CKD

Development Factor (rHuMGDF) and Recombinant  Alcoholics
Human Thrombopoietin (rHuTPO) – mixed results on  Liver disease

efficacy  Anticoagulants

o Mimics of recombinant thrombopoietin – used  Salicylates

exclusively for ITP  Barbiturates
 Romiplostim – small peptide that binds with high  Cefamandole
affiity to the thrombopoietin receptor
 o Usually occurs in newborns right after birth
 Safe and efficacious in patients with ITP
  clotting factors are 30 to 60% of adult values

 Platelet ct >50,000/μL in 8 weeks of study  due to reduced synthesis of precursor proteins and
 1-10 μg/kg/d SQ the sterility of their guts
 Eltrombopag – 6 week course of 50-75mg/d st
 Vit. K deficiency bleeding in 1 week of the infant's
orally life is 0.25 to 1.7%
o Well-tolerated  given especially in premature babies

2018-A DOMONDON, DUENAS, D UNGO, ENCARNACION, ENRIQUEZ 8OF13

Pharmacology 3.02
F. Tissue Plasminogen Activator (TPA) Inhibitors a day” dosing regimen for the patient. Which of the
 Used to control bleeding in patients following drugs will be best suited for the patient?
 Seen in the final stage of thrombin formation A. ferric-maltose complex 150 mg
 Inhibitors of fibrinolysis B. ferrous sulfate dessicated 325 mg
 Plasmin has a role in the lysis of clot made by secondary C. ferrous fumarate 200mg
hemostasis D. ferrous gluconate200 mg
4. Which of the following iron preparations is usually found
Aminocaproic acid in multivitamin medicated syrups because of its low
elemental iron content?
 Competes for lysine binding sites on plasminogen and A. ferrous gluconate
B. ferrous sulfate dessicated
plasmin, blocking the interaction of plasmin with fibrin

C. ferrous fumarate
 A very potent inhibitor of fibrinolysis (thrombi that formed
D. ferric-maltose complex
during treatment with the drug are not lysed)
 Used to reduce bleeding after prostatic surgery or after 5. Which of the following conditions associated with
tooth extractions in haemophiliacs cobalamin deficiency will benefit most from oral
 also used to prevent bleeding after surgical procedures cyanocobalamin?
(ability to treat a variety of bleeding disorders has been A. atrophic gastritis
unsuccessful) B. inflammatory bowel disease

st
Loading dose: 4-5g IV/PO during the 1 hour then 1-1.25g C. chronic alcoholism
PO q1Hour ; continuous IV infusion at 1g/Hr (continue for 8 D. ileal resection
hours or until bleeding is controlled, not to exceed 30g/day)
6. The conditions that will least likely benefit from epoeitin
Tranexamic acid
 alfa treatment
A. massive traumatic blood loss
 Like aminocaproic acid, competes for lysine binding sites B. chronic renal failure
on plasminogen and plasmin, thus blocking their interaction C. cancer
with fibrin D. AIDS
 Safer than aminocaproic acid
 57. Which of the following will most likely happen when
 Can be used for the same indications as aminocaproic correcting cobalamin deficiency with folic acid
acid and can be given IV or orally Usually given 1g 4x/day supplementation?
for 4 days (500mg 3x/day for 4-7days) A. lower incidence of homocysteinemia and venous thrombosis
B. lower incidence of megaloblastic anemia
*Adverse effects of both drugs: hypersensitivity reactions, C. decreased risk for nerve degeneration
nausea, vomiting, diarrhea, clotting problems (loss of vision, D. increased risk for neural tube defects
infarct, embolism) 
 8. In a patient with neutropenia, which of the following
agents will be least beneficial?
A. sargamostim
I. SUMMARY B. Romiplostim
 Erythropoietin stimulates erythropoiesis. (without it there C. filgrastim
will be no erythropoiesis that will happen) 
 D. perfilgrastim
 Iron is needed for maturation of RBC. 
 9. Thrombocytopenia from immunosuppressive
 Defective RBCs are formed in patients with Vit. B12 and B9 chemotherapy can be treated with the following

 are deficient. 
 medications EXCEPT:
 GM-CSF, G-CSF, IL-11 and thrombopoietin are helpful in A. elthrombopag

 certain conditions that produce neutropenia or B. romiplostim

 thrombocytopenia C. sargramostim
 Vit. K supplementation can be given to patients with certain D. Oprelvekin

 bleeding disirders. 10. Which of the following available vitamin K preparations is
 TPA inh. can be given to patients suffering bleeding from toxic for humans?

 trauma, surgery, etc. A. phylloquinone
B. menaquinone
GUIDE QUESTIONS C. menatetrenone
1. All of the following substances delay absorption of
D. menadione
ingested iron EXCEPT:
Answers:
A. caffeine
B. milk 1)C 2)C 3)C 4)A 5)C 6)A 7)B 8)B 9)C 10)D
C. sodium ascorbate OBJECTIVES
D. calcium ascorbate None.
2. Which of the following parenteral iron preparations has a REFERENCES
higher incidence of anaphylactic reactions? 1. Dr. Guevarra’s Lecture
A. ferric gluconate 2. Katzung
B. ferric sucrose 3. 2017B trans
C. ferric dextran
D. ferric oxide
3.Lexi, a 32-year-old female, diagnosed with iron deficiency
anemia, needs 60mg a day of elemental iron. To minimize
the incidence of adverse reactions, you decided on a “once

2018-A DOMONDON, DUENAS, D UNGO, ENCARNACION, ENRIQUEZ 9OF13

Pharmacology 3.02

2018-A DOMONDON, DUENAS, D UNGO, ENCARNACION, ENRIQUEZ 10OF13

Pharmacology 3.02
APPENDIX

Table 6: Vitamin K1 vs. Vitamin K2

Vitamin K1 Vitamin K2

Form Phylloquinone, Menaquinones, Bacteria in SI can convert

Phytomenadione, vit .K1 to K2
Phytonadione,

Source Leafy green vegetables: Animal Meat:

dandelion greens, spinach, lettuce
, cabbage, cauliflower, broccoli,
and brussels sprouts
Fruits:
avocado, kiwifruit and grapes
Absorption Small intestine
Signs and Symptoms of Anemia, bruising, bleeding gum or
Deficiency nose, heavy menstrual bleeding
Therapy At birth:
 IV: 0.5 to 1.0 mg
Newborns:
 Human milk (1–4 μg/L)
 Vit. K formula-derived milk
(100 μg/L)
chicken, beef, their fat, livers, and organs
Fermented or aged cheese, eggs

Bacteria in SI can convert K1 to K2
Small intestine
Deficiency Osteoporosis, Coronary heart
disease, Severe aortic calcification
Menopausal women:
 Orally (45 mg daily)
 To prevent osteoporosis
Rapid reversal from warfarin for pre-op:
 Orally (1-2.5 mg)

Figure 1: Events in Hemostasis

2018-A DOMONDON, DUENAS, D UNGO, ENCARNACION, ENRIQUEZ 11OF13

Pharmacology 3.02

Figure 2: Factors that favor and inhibit thrombosis

Figure 3: Myelopoiesis

2018-A DOMONDON, DUENAS, D UNGO, ENCARNACION, ENRIQUEZ 12OF13

Pharmacology 3.02

Figure 4: Megakaryopoiesis

2018-A DOMONDON, DUENAS, D UNGO, ENCARNACION, ENRIQUEZ 13OF13