4 Blood cology Public Health -rtttttttttttt pdf.pdf

Blood Pharmacology
By
Berhan Begashaw [ Bpharm, MSc in Pharmacology]
E-mail: berhan.uog1912@gmail.com
Department of Pharmacy
ASWHSC, DBU
Berhan B. [ Pharmacology Dep't] 1

Learning Objectives
After reading and studying this chapter the students will be
able to
 Describe how heparin and oral anticoagulants produce
their effect.
 Discuss the indication of heparin and oral anticoagulants
 Identify major adverse reactions associated with heparin
and oral anticoagulants
 Discuss the pharmacokinetics of iron,Vit B12 and folic acid.
 Explain the mechanisms of action of major anti anemic
drugs
 Discuss the use of iron to treat iron deficiency anemia, the
use ofVit B12 and folic acid to treat megaloblastic anemia.

Drugs that are useful in treating three important
dysfunctions of blood:
 anemia
 thrombosis
 bleeding
Thrombosis-formation of an unwanted clot within a
blood vessel, most common abnormality of
hemostasis.
Thrombotic disorders include acute MI, DVT,
pulmonary embolism, and acute ischemic stroke.
Rx with drugs such as anticoagulants & fibrinolytics.

 Bleeding disorders involving failure of hemostasis
are less common than thromboembolic diseases.
Include
Hemophilia,
which is treated with transfusion of Factor
VIII prepared by recombinant DNA techniques,
and
Vitamin K deficiency,
which is treated with dietary supplements of
vit-K.

BLOOD COAGULATION
Coagulation:
 is a cascade of proteolytic reaction
 Each protease factor activates the next
clotting factor in the sequence
Several of protease factors are targets for drug
therapy
Coagulants:
Are agents which promote coagulation and are
indicated in hemorrhagic states.
5
Berhan B. [ Pharmacology Dep't]

Drugs for hemostasis /drugs facilitate clotting:
Vitamin K: K1 [phytonadione]- fat soluble)
Action:
 Vitamin K is a cofactor in post translational
modification of clotting factors II,VII, IX and X

Pharmacokinetics:
 Vitamins K1 and K2 require bile salts for absorption
from the intestinal tract
 Vit K is only temporarily concentrated in liver
 Metabolized in liver and excreted in bile and urine
 Onset of effect is delayed for 6 hours but the
effect is complete by 24 hours when treating
depression of prothrombin activity by excess
warfarin or vitamin K deficiency

Use:
 Only in prophylaxis & treatment of bleeding due to
deficiency of clotting factors
 And in newborns, who are at risk of vit.K deficiency :
bleeding.
Adverse effects:
 Intravenous administration of vitamin K1 should be
slow,
- because rapid infusion can produce dyspnea,
chest and back pain, and even death

Anticoagulants
 Are drugs used to reduce the coagulability of
blood
A. Heparin [ Fast and direct acting]
B. Oral anticoagulants [ Slow and indirect acting]
 Warfarin
9

◦ Heparin
 Mechanism of anticoagulant action—Helps
antithrombimn III to inactivate coagulation -factor
(II,VII, IX, X)
 Pharmacokinetics—Cannot be given PO since can’t
cross CM & ineffective because it is inactivated by
gastric acids
Administration of heparin Iv, sc
Not administered im because of hematoma
formation at injection site
10

Heparin is often initiated as an intravenous bolus
to achieve immediate anticoagulation
Renal insufficiency prolongs the half-life of
LMWHs.
Therefore, the dose of LMWHs should be reduced
in patients with renal impairment
 Therapeutic uses
 Preferred during pregnancy & for situations
requiring rapid onset
 For pulmonary embolism, evolving stroke and
massive deep vein thrombosis (DVT)
 as well as patients undergoing open heart
surgery & renal dialysis

 Adverse effects —Hemorrhage, thrombocytopenia,
hypersensitivity reactions; local irritation &
hematoma from subcutaneous administration;
vasospastic reactions; long-term use with high
doses may cause osteoporosis.
 Anti-dote: Protamine sulfate
12

 Oral Anticoagulants—To prevent thrombosis;
delayed onset of action; not for emergency use;
carry significant risk of hemorrhage; risk amplified
by many drug interactions;
A. Warfarin —the oldest oral anticoagulant
 Mechanism of action—Antagonist of vitamin K
(factorsVII, IX, X and prothrombin).
13

Pharmacokinetics
 Readily absorbed after oral administration
 Hepatic metabolism & excretion in urine &feces
 Doesn’t affect clotting factors already present,
only those being synthesized (may be delayed 6
hours to 2.5 days)
 After discontinuing drug, effects still present for
2–5 days
14

 Therapeutic uses—Long-term prophylaxis of
thrombosis for those needing prevention of
pulmonary embolism, patients with prosthetic heart
valves, and those with atrial fibrillation
 Dose: 2.5 -7.5mg/day
 Adverse effects—Hemorrhage; fetal hemorrhage and
teratogenesis with use during pregnancy; not for
use during breast feeding;
—others (skin necrosis, alopecia, urticaria,
dermatitis, fever, GI disturbances, & red-
orange urine)
Anti-dote: Vitamin K1(phytonadione)
15

Drug interactions
—More interactions than probably any other drug;
 three major categories
- drugs that increase anticoagulant effects,
- drugs that promote bleeding, and
- drugs that decrease anticoagulant effects
 especially of concern are heparin, aspirin,
acetaminophen now thought to inhibit warfarin
degradation

Aspirin and phenylbutazone inhibit platelet
aggregation and hence
- potentiate warfarin action
Acute alcohol intoxication, Cimetidine,
cotrimoxazole , chloramphenicole and
metronidazole block metabolism of warfarin
-potentiate its effects.
Chronic alcohol consumption, barbiturates
,griseofulvin and rifampicin stimulate metabolism of
warfarin and
- decreases its effect.

Antiplatelet Drugs:
 Interfere with platelet function and may be useful
in the prophylaxis of thromboembolic disorders
Drugs interfering with platelet function:
 Aspirin
 Clopidogrol
 Others
 ASA: used as a long-term, at low doses, to help
prevent heart attacks, strokes, and blood clot
formation in people at high risk for developing
blood clots.
18

Aspirin
 Has an antiplatelet effect by inhibiting production
of thromboxane A2 which promotes platelet
aggregation.
 Low dose ( 80 mg po coated tablets) should be
used b/c at high dose, it also inhibits prostacycline
(PGI2 which prevents platelet aggregation)
 Also used long-term, at low doses, to help prevent
heart attacks, strokes, and blood clot formation in
people at high risk for developing blood clots.
 low doses of aspirin may be given immediately
after a heart attack to reduce the risk of another
heart attack or of the death.

Lipid Lowering Agents
Why Should we lower Lipids?
 To lower risk of
1. Coronary heart disease
 ed LDL associated with atherogenesis
 ed HDL associated with ed coronary vascular
diseases
2. Pancreatitis
 Associated with ed levels
20

Treatment of Hyperlipidemia
1. Treat underlying cause
2. Dietary treatment:
 Limit;- cholesterol intake
Saturated fat intake
 Limit total fat intake
 Limit simple sugar intake
3. Pharmacological;
 Dietary treatment should continue
 Statins: Atorvastatine, levostatin, etc.
21

Agents Used toTreat Anemia
◦ Anemia
 Defined as a below-normal plasma hemoglobin
concentration.
 Results from:
a decreased number of circulating RBCs
or
an abnormally low total hemoglobin
content per unit of blood volume.

 Anaemia occurs when balance b/n production
and destruction of RBCs is disturbed/caused by:
◦ Blood loss (acute or chronic)
◦ Impaired red cell formation:
due to deficiency of essential factors i.e. iron,
vitamin B12, folic acid
◦ bone marrow abnormalities
◦ infections, malignancy
◦ increased destruction of RBCs (haemolytic anaemia)
◦ drugs

 It can be at least temporarily corrected by
transfusion of whole blood.
A large number of drugs cause toxic effects on
blood cells, hemoglobin production, erythropoietic
organs, which in turn may cause anemia.
Nutritional anemias are caused by dietary
deficiencies such as iron, folic acid, or vitamin B12
(cyanocobalamin)
Anemia's caused by nutritional deficiencies, such as
the commonly encountered iron deficiency
anemia, can be treated with either dietary or
pharmaceutical supplementation.

Iron Deficiency Anemia (IDA)
 Most common cause of anemia
 Is manifestation of an underlying disease condition.
Common causes of IDA include:
 increased iron requirements ( pregnancy & lactation)
 blood loss (chronic bleeding, blood donation)
 worm infestation (hookworm), inadequate Fe supply
(malnutrition, malabsorption)
 The symptoms of IDA include;
fatigue,
headache,
tinnitus, palpitations,
sore tongue and dysphagia.

Drug therapy of IDA
 Ferrous sulfate, ferrous gluconate, ferrous fumarate
 S/Es: Nausea, abdominal cramps & dyspeptic
symptoms, constipation or diarrhea.
 Patients who do not tolerate ferrous sulfate tablets
may be advised to take it with meals, or to start a
smaller dose, or to change the brand to ferrous
gluconate or fumarate tablets.
 D/Is: Antacids, tetracyclines, etc. interfere with the
absorption & metabolism of iron.

Alternative
Iron dextran injection.
S/Es: Pain, swelling, staining at site of injection; nausea,
vomiting, taste disturbances; hypersensitivity
reactions.
C/Is: History of allergic reactions (including asthma);
severe hepatic or renal impairment; pregnancy.

N.B.
 Iron parenteral therapy is rarely indicated.
 indications include;
 Oral iron intolerance,
Mal-absorption, presence of an inflammatory
bowl
active peptic ulcer disease,
inability or unwillingness by the patient to take
oral Fe.
A dose of 25mg (0.5ml) IV is given first to test
for hypersensitivity reactions and the patient is
observed closely for possible complications.

Megaloblastic Anemia (MA)
 >95% of MA is due to deficiency or unbalanced
metabolism of either cobalamin (vitamin B12) or
folate, cofactors required for the normal maturation
of red blood cells.
 Folate deficiency MA is more common in Ethiopians.
 Folate deficient patients are usually malnourished.
 Poor absorption of Vit B12

 Folate deficiency may be caused by
1. increased demand ( pregnancy and lactation)
2. poor absorption caused by pathology of the
small intestine,
3. alcoholism
4. Rx with drugs that are dihydrofolate reductase
inhibitors(methotrexate, pyrimethamine, and
trimethoprim).
folinic acid—also known as leucovorin calcium

 Neuropsychiatric manifestations /neurologic defects
are encountered in cobalamin deficiency, but not in
folate deficiency states.
 may become irreversible if not treated promptly
 Neuropsychiatric manifestations include;
confusion; memory changes; delirium, hallucinations
and/or delusions;
 depression; acute psychotic states; and (more
rarely) reversible manic and schizophreniform states.

Treatment of MA
 Vitamin B12(Cyanocobalamine)
 Because vitamin B12 deficiency anemia is almost
always caused by inadequate absorption, therapy
should be by replacement of vitamin B12
 S/Es: Itching, fever chills, hot flushes, nausea and
dizziness.

Folic acid (Folate deficiency MA)
 Because maternal folic acid deficiency is associated
with increased risk of neural tube defects in the
fetus,
folic acid supplementation is recommended before
and during pregnancy.
 Folic acid supplements correct the anemia but not
the neurologic deficits of vitamin B12 deficiency.
 Therefore, vitamin B12 deficiency must be ruled out
before one selects folic acid as the sole therapeutic
agent in the treatment of a patient with MA.

N.B.
 The hematologic picture normalizes in about 2 months
in both cobalamine and folate replacement therapy.
 Large doses of folate may produce hematologic
response in cobalamine deficiency states.
 This masks the cobalamine deficiency state and allows
the neurologic damage to progress.
 Therefore, if both folate and cobalamine are deficient,
cobalamine is administered first, followed by folate.
 Blood transfusion with packed RBCs could be needed
in severe cases.

Does deficiency of iron occurs most often in women or
men?
Why?
……………………………………………………
……………………………………………………
………………………………………………………
…….

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4 Blood cology Public Health -rtttttttttttt pdf.pdf