DRUGS WITH ACTION ON BLOOD—

TOPIC – Agents used in anemias and haemopoetic growth factors

BLOOD CELL DEFICIENCIES—

1. Iron and vitamin deficiency anemia

 Microcytic hypochromic anemia, caused by iron deficiency, is the most
common type of anemia.
 Megaloblastic anemias are caused by a deficiency of vitamin B 12 or folic
acid,
 Pernicious anemia, the most common type of vitamin B12 deficiency
anemia, is caused by a defect in the synthesis of intrinsic factor,
2. OTHER BLOOD CELL DEFICIENCY –
 Deficiency in the concentration of the various lineages of blood cells can be
a manifestation of a disease or a side effect of radiation or cancer
chemotherapy.

IRON –
 Iron is the essential metallic component of heme, the molecule responsible
for the bulk of oxygen transport in the blood.
 most of the iron in the body is contained in hemoglobin
 , an important fraction is bound to transferrin
 and ferritin, a storage protein.

REGULATION OF IRON STORES –

Absorption—
2+
 Dietary iron in the form of heme and the ferrous ion (Fe ) are taken up by
specialized transporters on the luminal surface of intestinal epithelial cells
 Intestinal cell iron is either stored as ferritin
 the ferrous iron is transported across the basolateral membrane by ferroportin
and oxidized to ferric iron

Transport and storage

 Ferric iron is transported in a complex with transferrin

 Excess iron is stored in the protein-bound form in gastrointestinal epithelial
cells, macrophages, and hepatocytes, and in cases of gross overload, in
parenchymal cells of the skin, heart, and other organs.

Elimination—

Minimal amounts of iron are lost from the body with sweat and saliva and in
exfoliated skin and intestinal mucosal cells.

CLINICAL USE—
Prevention or treatment of iron deficiency anemia is the only indi- cation for iron
administration.

Iron deficiency can be diagnosed from red blood cell changes

The disease is treated by dietary ferrous iron supplementation with ferrous sulfate,
ferrous gluconate, or ferrous fumarate.

In special cases, treatment is by parenteral administration of a colloid containing a

core of iron oxyhydroxide surrounded by a core of carbohydrate.

Parenteral iron prepara- tions include iron dextran, sodium ferric gluconate
complex, and iron sucrose.

TOXICITY OF IRON –

1. Signs and symptoms—

Acute iron intoxication is most common in children and usually occurs as a result of
accidental ingestion of iron supplementation tablets.

Depending on the dose of iron, necrotizing gastroenteritis, shock, metabolic acidosis,

coma, and death may result.

Chronic iron overload, known as hemochromatosis, damages the organs that store
excess iron (heart, liver, pancreas).

Hemochromatosis occurs most often in individuals with an inherited abnormality of

iron absorption and those who receive frequent transfusions for treatment of hemolytic
disorders (eg, thalassemia major).

2.Treatment of acute iron intoxication—

Immediate treatment is necessary

consists of removal of unabsorbed tablets from the gut

parenteral administration of deferoxamine, which chelates circulating iron.

3. Treatment of chronic iron toxicity—

Treatment of the genetic form of hemochromatosis is usually by phlebotomy.

Hemochromatosis that is due to frequent transfusions is treated with parenteral

deferoxamine or with the newer oral iron chelator deferasirox.

VITAMIN B12---

A.ROLE OF VITAMIN B12 –

Vitamin B12 (cobalamin), a cobalt-containing molecule, is, along with folic acid

a step necessary for the synthesis of DNA. Impairment of DNA synthe- sis affects all
cells,

In addition, vitamin B12 deficiency can cause neurologic defects, which may become
irreversible if not treated promptly.

B.PHARMACOKINETICS

Vitamin B12 is produced only by bacteria; this vitamin cannot be synthesized by

multicellular organisms.

It is absorbed from the gastrointestinal tract in the presence of intrinsic factor, a

product of the parietal cells of the stomach.

Plasma transport is accom- plished by binding to transcobalamin II.

Vitamin B12 is stored in the liver in large amounts; a normal individual has enough to
last 5 yrs.

The 2 available forms of vitamin B12, cyanocobalamin and hydroxocobalamin, have

similar pharmacokinetics, but hydroxo- cobalamin has a longer circulating half-life.

C.PHARMACODYNAMICS –

 Vitamin B12 is essential in 2 reactions: conversion of methylmalonyl- coenzyme

A (CoA) to succinyl-CoA and conversion of homocys- teine to methionine.
 The second reaction is linked to folic acid metabolism and synthesis of
deoxythymidylate
 Administration of folic acid to patients with vitamin B12 deficiency helps refill
the tetrahydrofolate pool
 partially or fully corrects the anemia.
 However, the exogenous folic acid does not correct the neurologic defects of
vitamin B12 deficiency.

D.CLINICAL USE AND TOXICITY –

 The 2 available forms of vitamin B12—hydroxocobalamin and cyanocobalamin

—have equivalent effects.
 is in the treatment of naturally occurring pernicious anemia and anemia caused
by gastric resection.
 Because vitamin B12 deficiency anemia is almost always caused by inadequate
absorption, therapy should be by replacement of vitamin B12, using parenteral
therapy.
 FOLIC ACID –

A.ROLE OF FOLIC ACID –

 Like vitamin B12, folic acid is required for normal DNA synthesis, and its
deficiency usually presents as megaloblastic anemia.
 deficiency of folic acid during pregnancy increases the risk of neural tube
defects in the fetus.

B.PHARMACOKINETICS—

 Folic acid is readily absorbed from the gastrointestinal tract.

 Only modest amounts are stored in the body

C.PHARMACODYNAMICS ---

 Folic acid is converted to tetrahydrofolate by the action of dihydrofolate

reductase
 One impor- tant set of reactions involving tetrahydrofolate and dihydro- folate
constitutes the dTMP cycle
 Rapidly dividing cells are highly sensitive to folic acid deficiency.

D.CLINICAL USE AND TOXICITY

 Folic acid deficiency is most often caused by dietary insufficiency or

malabsorption.
 Anemia resulting from folic acid deficiency is readily treated by oral folic acid
supplementation.
 folic acid supplementation is rec- ommended before and during pregnancy.
 Folic acid supplements correct the anemia but not the neurologic deficits of
vitamin B12 deficiency.

HAEMOPOIETIC GROWTH FACTORS –

More than a dozen glycoprotein hormones that regulate the dif- ferentiation and
maturation of stem cells within the bone marrow have been identified.

A. Erythropoiesis-Stimulating Agents (ESAs)

 Erythropoietin is produced by the kidney; reduction in its synthesis underlies
the anemia of renal failure.
 Through activation of receptors on erythroid progenitors in the bone marrow,
erythro- poietin stimulates the production of red cells and increases their
release from the bone marrow.
 Erythropoiesis-stimulating agents (ESAs) are routinely used for the anemia
associated with renal failure and are sometimes effective for patients with other
forms of anemia
 As an alternative to recombinant human erythropoietin (epoetin alfa),
 darbepoetin alfa, a glycosylated form of erythropoietin, has a much longer
half-life.
 Methoxy polyethylene glycol-epoetin beta is a long-lasting form of
erythropoietin that can be administered once or twice a month.
 The most common complications of ESA therapy are hyper- tension and
thrombosis.

B. Myeloid Growth Factors

 Filgrastim (granulocyte colony-stimulating factor; G-CSF) and sargramostim
(granulocyte-macrophage colony-stimulating factor; GM-CSF) stimulate the
production and function of neutrophils.
 GM-CSF also stimulates the production of other myeloid and megakaryocyte
progenitors.
 G-CSF and, to a lesser degree, GM-CSF mobilize hematopoietic stem cells
 Both growth factors are used to accelerate the recovery of neu- trophils after
cancer chemotherapy and to treat other forms of sec- ondary and primary
neutropenia
 When given to patients soon after autologous stem cell transplantation, G-CSF
reduces the time to engraftment and the duration of neutropenia.
 G-CSF is also used to mobilize peripheral blood stem cells in preparation for
autologous and allogeneic stem cell transplantation.
 . The toxicity of G-CSF is minimal, although the drug sometimes causes bone
pain. GM-CSF can cause more severe effects, including fever, arthralgias, and
capillary damage with edema. Allergic reactions are rare
 Pegfilgrastim, a covalent conjugation product of filgrastim and a form of
polyethylene gly- col, has a much longer serum half-life than recombinant G-
CSF.
 Lenograstim, used widely in Europe, is a glycosylated form of recombinant G-
CSF.

C. Megakaryocyte Growth Factors

 Oprelvekin (interleukin-11 [IL-11]) stimulates the growth of primitive
megakaryocytic progenitors and increases the number of peripheral platelets.
 IL-11 is used for the treatment of patients who have had a prior episode of
thrombocytopenia after a cycle of cancer chemotherapy.
 In such patients, it reduces the need for platelet transfusions.
 The most common adverse effects of IL-11 are fatigue, headache, dizziness,
and fluid retention.
 Romiplostim, a thrombopoietin receptor agonist with a novel peptide structure,
is used subcutaneously in patients with chronic idiopathic thrombocytopenia
who have failed to respond to conventional treatment
 Eltrombopag is an oral agonist of the thrombopoietin receptor that is also used
for patients with chronic idiopathic thrombocytopenia that is refractory to other
agents.
TOPIC – DRUGS USED IN COAGULATION DISORDERS –

The drugs used in clotting and bleeding disorders fall into 2 major groups:

(1) drugs used to decrease clotting or dissolve clots already present in patients at risk
for vascular occlusion

(2) drugs used to increase clotting in patients with clotting deficiencies.

Anticlotting drugs are used in the treatment and prevention of myocardial infarction
and other acute coronary syndromes, atrial fibrillation, ischemic stroke, and deep vein
thrombosis (DVT).

ANTICOAGULANTS ---
A.CLASSIFICATION –
 inhibit the formation of fibrin clots.
 Three major types of anticoagulants are available: heparin and related products,
which must be used parenterally;
 irect thrombin and factor X inhibitors, which are used parenterally or orally;
and the orally active coumarin derivatives

B.HEPARIN—
1.chemistry ---
 large sulfated polysaccharide polymer obtained from animal sources
 Heparin is highly acidic and can be neutralized by basic molecules
 Heparin is given intravenously or subcutane- ously to avoid the risk of
hematoma associated with intramuscular injection.
 Low-molecular-weight (LMW) fractions of heparin (eg, enoxaparin) have
molecular weights of 2000–6000.
 heparins have greater bioavailability and longer durations of action than
unfractionated heparin; thus, doses can be given less frequently
 They are given subcutane- ously.
 Fondaparinux is a small synthetic drug that contains the biologically active
pentasaccharide present in unfractionated
 administered subcutaneously

2. Mechanism and effects—

 Unfractionated heparin binds to endogenous antithrombin III (ATIII) via a

key pentasaccharide sequence
 The heparin–ATIII complex combines with and irrevers- ibly inactivates
 thrombin and several other factors, particularly factor Xa
 In the presence of heparin, ATIII proteo- lyzes thrombin and factor Xa
approximately 1000-fold faster than in its absence.
 Because it acts on preformed blood components, heparin provides
anticoagulation immediately after administration.
 The action of heparin is monitored with the activated partial thromboplastin
time (aPTT) laboratory test.
 LMW heparins and fondaparinux, like unfractionated heparin, bind ATIII.
 have the same inhibitory effect on factor Xa as the unfractionated heparin–
ATIII complex.
 short-chain heparin–ATIII and fondaparinux–ATIII complexes provide a more
selective action because they fail to affect thrombin.
 The aPTT test does not reliably measure the anticoagulant effect of the LMW
heparins and fondaparinux

3. Clinical use—

 its rapid effect

 heparin is used when anticoagulation is needed immediately
 Common uses include treatment of DVT, pulmonary embolism, and acute
myocardial infarction.
 used in combination with thrombolytics for revascularization and in com-
bination with glycoprotein IIb/IIIa inhibitors during angioplasty and placement
of coronary stents.
 does not cross the placental barrier, heparin is the drug of choice when an
anticoagu- lant must be used in pregnancy.

4.Toxicity—

 Increased bleeding is the most common adverse effect of heparin and related
molecules
 may result in hemorrhagic stroke.
 Protamine can lessen the risk of serious bleeding that can result from
excessive unfractionated heparin.
 Protamine only partially reverses the effects of LMW heparins and does not
affect the action of fondaparinux.
 Unfractionated heparin causes moderate transient thrombocytopenia
 severe thrombocytopenia and thrombosis (heparin-induced thrombocytopenia
or HIT) in a small per- centage of patients who produce an antibody that binds
to a complex of heparin and platelet factor 4.
 LMW heparins and fondaparinux are less likely to cause this immune-mediated
thrombocytopenia.

C.DIRECT THROMBIN INHIBTORS –

1. Chemistry and pharmacokinetics

 are based on proteins made by Hirudo medicinalis,

 Lepirudin is the recombinant form of the leech protein hirudin,
 while desirudin and bivalirudin are modified forms of hirudin.
 . Argatroban is a small molecule with a short half-life.
 Dabigatran is an orally active direct thrombin inhibitor.

2. Mechanism and effects—

 The protein analogs of lepirudin bind simultaneously to the active site of

thrombin and to throm- bin substrates
 . Argatroban binds solely to the thrombin-active site.
 these drugs inhibit both soluble thrombin and the thrombin enmeshed within
developing clots.
 Bivalirudin also inhibits platelet activation.

3.Clinical use—

 Direct thrombin inhibitors are used as alterna- tives to heparin

 in patients with heparin-induced throm- bocytopenia.
 Bivalirudin also is used in combination with aspirin during percutaneous
coronary angioplasty.

4.toxicity ---

 , the direct thrombin inhibi- tors can cause bleeding

 No reversal agents exist
 can induce anaphylactic reactions.

D. Direct Oral Factor Xa inhibitors

1. Chemistry and pharmacokinetics—

 Oral Xa inhibitors, including the small molecules rivaroxaban and apixaban,

have a rapid onset of action and shorter half-lives than warfarin.
 They undergo cytochrome P450-dependent and cytochrome P450-independent
elimination.

2. Mechanism and effects—

 These small molecules directly bind to and inhibit both free factor Xa and
factor Xa bound in the clotting complex.

3.Clinical use—

 Rivaroxaban is approved for prevention of venous thromboembolism following

hip or knee surgery
4. Toxicity—Like other anticoagulants, the factor Xa inhibitors can cause bleeding.
No reversal agents exist.

E. Warfarin and Other Coumarin Anticoagulants

1. Chemistry and pharmacokinetics—

 Warfarin and other coumarin anticoagulants are small, lipid-soluble molecules

that are readily absorbed after oral administration.
 Warfarin is highly bound to plasma proteins (99%), and its elimination
depends on metabolism by cytochrome P450 enzymes.

2. Mechanism and effects—

 Warfarin and other coumarins interfere with the normal post-translational

modification of clotting factors in the liver, a process that depends on an
adequate supply of reduced vitamin K.
 The drugs inhibit vitamin K epoxide reductase (VKOR), which normally
converts vitamin K epoxide to reduced vitamin K.
 . Because the clotting factors have half-lives of 8–60 h in the plasma, an
anticoagulant effect is observed only after sufficient time has passed for
elimination of the normal preformed factors
 The action of warfarin can be reversed with vitamin K, but recovery
requires the synthesis of new normal clotting factors and is, therefore, slow
(6–24 h)
 More rapid reversal can be achieved by transfusion with fresh or frozen
plasma that contains normal clotting factors. The effect of warfarin is
monitored by the prothrombin time (PT) test.

3. Clinical use—Warfarin is used for chronic anticoagulation in all of the clinical

situations described previously for heparin, except in pregnant women.
4. 4. Toxicity—Bleeding is the most important adverse effect of warfarin. Early
in therapy, a period of hypercoagulability with subsequent dermal vascular
necrosis can occur. This is due to deficiency of protein C, an endogenous
vitamin K-dependent anticoagulant with a short half-life. Warfarin can cause
bone defects and hemorrhage in the developing fetus and, therefore, is
contraindicated in pregnancy.

THROMBOLYTIC AGENTS
A. Classification and Prototypes

The thrombolytic drugs used most commonly are either forms of the endogenous
tissue plasminogen activator (t-PA; eg, alteplase, tenecteplase, and reteplase) or a
protein synthesized by streptococci (streptokinase).

B. Mechanism of Action
Plasmin is an endogenous fibrinolytic enzyme that degrades clots by splitting fibrin
into fragments

1. Tissue plasminogen activator—t-PA is an enzyme that directly converts

plasminogen to plasmin (Figure 34–2).

little activity unless it is bound to fibrin, which, in theory, should make it selective for
the plasminogen that has already bound to fibrin (ie, in a clot) and should result in less
danger of widespread production of plasmin and spontaneous bleeding. In fact, t-PA’s
selectivity appears to be quite limited. Alteplase is normal human plasminogen
activator. Reteplase is a mutated form of human t-PA with similar effects but a
slightly faster onset of action and longer duration of action. Tenecteplase is another
mutated form of t-PA with a longer half-life.

2. Streptokinase—Streptokinase is obtained from bacterial cultures. Although not

itself an enzyme, streptokinase forms a complex with endogenous plasminogen; the
plasminogen in this complex undergoes a conformational change that allows it to
rapidly convert free plasminogen into plasmin. Unlike the forms of t-PA,
streptokinase does not show selectivity for fibrin-bound plasminogen.

C. ClinicalUse
The major application of the thrombolytic agents is as an alter- native to percutaneous
coronary angioplasty in the emergency treatment of coronary artery thrombosis.
Under ideal conditions (ie, treatment within 6 h), these agents can promptly recanalize
the occluded coronary vessel. Very prompt use (ie, within 3 h of the first symptoms)
of t-PA in patients with ischemic stroke is associated with a significantly better
clinical outcome. Cerebral hemorrhage must be positively ruled out before such use.
The thrombolytic agents are also used in cases of severe pulmonary embolism.

D. Toxicity Bleeding is the most important hazard and has about the same
frequency with all the thrombolytic drugs. Cerebral hemorrhage is the most serious
manifestation. Streptokinase, a bacterial pro- tein, can evoke the production of
antibodies that cause it to lose its effectiveness or induce severe allergic reactions on
subsequent therapy. Patients who have had streptococcal infections may have
preformed antibodies to the drug. Because they are human proteins, the recombinant
forms of t-PA are not subject to this problem. However, they are much more
expensive than streptoki- nase and not much more effective.