Blood and blood forming agents

Blood and blood forming agents

Oral anticoagulants:

i.        Coumarin derivates: bishydroxycoumarin, warfarin sodium, ethylbiscoumacetate

ii.      Indandione derivatives: Phenindione

Pharmacological Actions of Warfarin

a.       It is used both on inpatient and outpatient basis when long-term anticoagulant therapy is indicated.

b.      The onset of anticoagulation is delayed, the latency determined by time required for absorption and by half-lives of vitamin K–dependent hemostatic proteins.

c.       The anticoagulant effect will not be evident in coagulation tests such as prothrombin time until normal factors already present in blood are catabolized; this takes 5 hours for factor VII and 2 to 3 days for prothrombin (factor II).

d.      The anticoagulant effect preceded by transient period of hypercoagulability due to rapid decrease in protein C levels. More rapid anticoagulation is provided, when necessary, by administering heparin.

e.       Warfarin is administered in conventional doses or minidoses to reduce bleeding.

Mechanism of Action

Unlike heparin, oral anticoagulants induce hypocoagulability only in vivo. They are vitamin K antagonists. Vitamin K is required to catalyze conversion of precursors of vitamin K–dependent clotting factors II, VII, IX, and X.This involves posttranslational α-carboxylation of glutamic acid residues at N-terminal end of proteins. The α-carboxylation step is linked to cycle of enzyme reactions involving active hydroquinone form of vitamin K. The regeneration of K1H1 by epoxide reductase is blocked by oral anticoagulants. These drugs thus cause hypocoagulability by inducing formation of structurally incomplete clotting factors.

Warfarin is used for:

1.      Prevention (prophylaxis) and treatment of DVT

2.      Prevention and treatment of atrial fibrillation with embolization

3.      Prevention and treatment of PE

4.      As part of the treatment of MI

5.      Prevention of thrombus formation after valve replacement

6.      In most situations, warfarin is the drug of choice, with anisindione reserved for those who are unable to take warfarin.

ADVERSE REACTIONS

Bleeding, which may range from very mild to severe. Bleeding may be seen in many areas of body, such as bladder, bowel, stomach, uterus, and mucous membranes. Others are rare but may include nausea, vomiting, alopecia, urticaria, abdominal cramping, diarrhea, rash, hepatitis, jaundice, and blood dyscrasias.

CONTRAINDICATIONS

Warfarin is contraindicated in patients with known hypersensitivity to drug, hemorrhagic disease, tuberculosis, leukemia, uncontrolled hypertension, GI ulcers, recent surgery of eye or central nervous system, aneurysms, or severe renal or hepatic disease, and during pregnancy and lactation. Use during pregnancy (Pregnancy Category X) can cause fetal death

Thrombolytics

Thrombolytic (Fibrinolytic) Drugs cause lysis of formed clots in both arteries and veins and re-establish tissue perfusion.

Mechanism of Action

Thrombolytic drugs are plasminogen activators. It rapidly lyse thrombi by catalyzing the formation of serine protease plasmin from its precursor zymogen, plasminogen. These drugs create a generalized lytic state when administered intravenously. Thus, both protective hemostatic thrombi and target thromboemboli are broken down.

Pharmacology

Streptokinase is a protein (but not an enzyme in itself) synthesized by streptococci that combines with the proactivator plasminogen. This enzymatic complex catalyzes conversion of inactive plasminogen to active plasmin.

Uses: Acute myocardial infarction, acute ischemic stroke, pulmonary embolism, DVT,

Adverse effects: - Minor bleeding (superficial and surface) and major bleeding.

Urokinase is a human enzyme synthesized by kidney that directly converts plasminogen to active plasmin. Plasmin itself cannot be used because naturally occurring inhibitors in plasma prevent its effects. Absence of inhibitors for urokinase and streptokinase-proactivator complex permit their use clinically. Plasmin formed inside thrombus by these activators is protected from plasma antiplasmins, which allows it to lyse thrombus from within.

Uses: Acute myocardial infarction, acute ischemic stroke, pulmonary embolism, DVT,

Adverse effects: - Minor bleeding (superficial and surface) and major bleeding.

Alteplase:Human t-PA is manufactured as alteplase by means of recombinant DNA technology.

Uses: lysis of coronary artery thrombi, IV catheter clearance, pulmonary embolism

Adverse effects: - Bleeding (GI, GU, or at injection site), intracranial hemorrhage, anemia

Reteplase is another recombinant human t-PA from which several amino acid sequences have been deleted. It is less expensive to produce than t-PA. Because it lacks major fibrin-binding domain, reteplase is less fibrin-specific than t-PA.

Uses: Acute myocardial infarction,

Adverse effects: - Bleeding (GU, gingival, retroperitoneal), and epistaxis, ecchymosis

Tenecteplase is a mutant form of t-PA that has longer half-life, and can be given intravenous bolus. Tenecteplase is slightly more fibrin-specific than t-PA.

Uses: Acute myocardial infarction, acute ischemic stroke, pulmonary embolism, DVT,

Adverse effects: - Bleeding (GI, GU, or at injection site), intracranial hemorrhage, anemia

Contraindications include active bleeding, cardiopulmonary resuscitation, intracranial trauma, vascular disease, and cancer. Relative contraindications include uncontrolled hypertension, earlier central nervous system surgery, and any known bleeding risk.

Anti-coagulants

Classification

1.      Used in vivo

A.    Parenteral anticoagulants: heparin, low mol. Wt. heparin, heparinoids, danaparoid, lepirudin,

B.     Oral anticoagulants:

iii.    Coumarin derivates: bishydroxycoumarin, warfarin sodium, ethylbiscoumacetate

iv.    Indandione derivatives: Phenindione

2.      Used in vitro

Ex: Heparin, calcium complexing agents: sodium citrate

Heparin (heparin sodium) is mixture of highly electronegative acidic mucopolysaccharides that contain numerous N- and O-sulfate linkages. It is produced by

and can be released from mast cells and is abundant in liver, lungs, and intestines.

Mechanism of Action

It depends on presence of specific serine protease inhibitor (serpin) of thrombin, antithrombin III, in normal blood. Heparin binds to antithrombin III and induces conformational change that accelerates interaction of antithrombin III with coagulation factors. Heparin also catalyzes inhibition of thrombin by heparin cofactor II, a circulating inhibitor. Smaller amounts of heparin are needed to prevent formation of free thrombin than are needed to inhibit protease activity of clot-bound thrombin.

Adverse Effects

a.       Hemorrhage, bleeding can occur in urinary or gastrointestinal tract and in adrenal gland.

b.      Subdural hematoma, acute hemorrhagic pancreatitis, hemarthrosis, and wound ecchymosis also occur.

c.       Heparin-induced thrombocytopenia of immediate and delayed onset may occur in 3 to 30% of patients.

d.      The immediate type is transient and may not involve platelet destruction, while delayed reaction involves production of heparin-dependent antiplatelet antibodies and clearance of platelets from blood.

e.       Heparin-associated thrombocytopenia may be associated with irreversible aggregation of platelets (white clot syndrome).

f.       It includes hypersensitivity reactions (e.g., rash, urticaria, pruritus), fever, alopecia, hypoaldosteronism, osteoporosis, and osteoalgia.

USES

1.      Prevention and treatment of venous thrombosis, PE, peripheral arterial embolism;

2.      Atrial fibrillation with embolus formation;

3.      Prevention of postoperative venous thrombosis (DVT) and PE in certain patients undergoing surgical procedures, such as major abdominal surgery;

4.      Prevention of clotting in arterial and heart surgery, in blood transfusions and dialysis procedures, and in blood samples for laboratory purposes;

5.      Prevention of repeat cerebral thrombosis in patients who have experienced stroke;

6.      Treatment of coronary occlusion, acute MI, and peripheral arterial embolism;

7.      Prevention of clotting in equipment used for extracorporeal circulation;

8.      Diagnosis and treatment of disseminated intravascular coagulation, a severe hemorrhagic disorder.

9.      Maintenance of patency of IV catheters.

10.  The LMWHs are used to prevent DVT after certain surgical procedures, such as hip or knee replacement surgery or abdominal surgery.

11.  The drugs are also used for ischemic complications of unstable angina and MI.

Heparin

Pharmacological Actions

a.       The physiological function of heparin is not completely understood.

b.      It is found only in trace amounts in normal circulating blood.

c.       It exerts an antilipemic effect by releasing lipoprotein lipase from endothelial cells; heparin like proteoglycans produced by endothelial cells have anticoagulant activity.

d.      Heparin decreases platelet and inflammatory cell adhesiveness to endothelial cells, reduces release of platelet-derived growth factor, inhibits tumor cell metastasis, and exerts an antiproliferative effect on smooth muscle.

e.       Heparin inhibits both in vitro and in vivo clotting of blood. Whole blood clotting time and activated partial thromboplastin time (aPTT) are prolonged in proportion to blood heparin concentrations.

Absorption, Metabolism, and Excretion

a.       Not absorbed after oral administration and must be given parenterally.

b.      Intravenous administration results in an almost immediate anticoagulant effect.

c.       There is an approximate 2-hour delay in onset of drug action after subcutaneous administration.

d.      Intramuscular injection is to be avoided because of unpredictable absorption rates, local bleeding, and irritation.

e.       Heparin is not bound to plasma proteins or secreted into breast milk, and it does not cross placenta.

f.       Heparin’s action is terminated by uptake and metabolism by reticuloendothelial system and liver and by renal excretion of unchanged drug and its depolymerized and desulfated metabolite.

Adverse Effects

g.      Hemorrhage, bleeding can occur in urinary or gastrointestinal tract and in adrenal gland.

h.      Subdural hematoma, acute hemorrhagic pancreatitis, hemarthrosis, and wound ecchymosis also occur.

i.        Heparin-induced thrombocytopenia of immediate and delayed onset may occur in 3 to 30% of patients.

j.        The immediate type is transient and may not involve platelet destruction, while delayed reaction involves production of heparin-dependent antiplatelet antibodies and clearance of platelets from blood.

k.      Heparin-associated thrombocytopenia may be associated with irreversible aggregation of platelets (white clot syndrome).

l.        It includes hypersensitivity reactions (e.g., rash, urticaria, pruritus), fever, alopecia, hypoaldosteronism, osteoporosis, and osteoalgia.

Hematinics

Hematinics are the substances required in the formation of blood, and are used for treatment of anemias.

Classification:

1.      Iron

a.       Oral: ferrous sulfate, ferrous fumarate, ferrous gluconate, ferrous succinate, colloidal ferric hydroxide, iron hydroxyl polymaltose, ferric ammonium citrate, iron calcium complex

b.      Parenteral: iron-dextran, iron-sorbitol-citric acid

2.      Maturation factors

a.       Vitamin B_12: Cyanocobalamin, Hydroxy coblamin, methyl cobalamin

b.      Folic acid, folinic acid

3.      Miscellaneous: copper, pyridoxine, riboflavin.

Iron

ACTIONS AND USES

Iron salts, such as ferrous sulfate or ferrous gluconate, are used in treatment of iron deficiency anemia, which occurs when there is a loss of iron that is greater than available iron stored in body. Iron preparations act by elevating serum iron concentration, which replenishes hemoglobin and depleted iron stores.

Iron dextran is a parenteral iron that is also used for the treatment of iron deficiency anemia. It is primarily used when the patient cannot take oral drugs or when patient experiences gastrointestinal intolerance to

oral iron administration.

ADVERSE REACTIONS

Iron salts cause gastrointestinal irritation, nausea, vomiting, constipation, diarrhea, headache, backache, and allergic reactions. The stools appear darker (black).

Iron dextran is given by parenteral route. Hypersensitivity reactions, including fatal anaphylactic reactions, have been reported with use of this form of iron.

Additional adverse reactions include soreness, inflammation, and sterile abscesses at the intramuscular injection site. Intravenous administration may result in phlebitis at injection site.

When iron is administered via the IM route, a brownish discoloration of skin may occur. Patients with rheumatoid arthritis may experience an acute exacerbation of joint pain, and swelling may occur when iron dextran is administered.

CONTRAINDICATIONS, PRECAUTIONS, AND INTERACTIONS

a.       Drugs used to treat anemia are contraindicated in patients with known hypersensitivity to drug.

b.      Iron compounds are contraindicated in patients with any anemia except iron deficiency anemia.

c.       Iron compounds are used cautiously in patients with tartrazine or sulfite sensitivity because some iron compounds contain these substances.

d.      The iron preparations are used cautiously during pregnancy and lactation. Iron dosages of 15 to 30 mg/d are sufficient to meet needs of pregnancy.

e.       Iron dextran is used cautiously in patients with cardiovascular disease, a history of asthma or allergies, and rheumatoid arthritis.

f.       The absorption of oral iron is decreased when agent is administered with antacids, tetracyclines, penicillamine, and the fluoroquinolones.

g.      When iron is administered with levothyroxine, there may be decrease in effectiveness of levothyroxine.

h.      When administered orally, iron decreases absorption of levodopa. Ascorbic acid increases absorption of oral iron.

i.        Iron dextran administered concurrently with chloramphenicol increases serum iron levels.

Erythropoietin

ACTIONS AND USES

Epoetin alfa is drug that is produced using recombinant DNA technology. The drug acts in a manner similar to that of natural erythropoietin. Epoetin alfa is used to treat anemia associated with chronic renal failure, anemia in patients with cancer who are receiving chemotherapy, and in patients with anemia who are undergoing elective nonvascular surgery. The drug is used to treat anemia associated with chronic renal failure in patients receiving dialysis as well as for patients who are not receiving dialysis. These drugs elevate or maintain RBC levels and decrease need for transfusions.

ADVERSE REACTIONS include hypertension, headache, tachycardia, nausea, vomiting, diarrhea, skin rashes, fever, myalgia, and skin reaction at the injection site.

CONTRAINDICATIONS, PRECAUTIONS, AND INTERACTIONS

Epoetin alfa is contraindicated in patients with uncontrolled hypertension, those needing an emergency transfusion, or those with a hypersensitivity to human albumin. Epoetin alfa are used with caution in patients with hypertension, heart disease, congestive heart failure, or a history of seizures. These are used cautiously during pregnancy and lactation.

Folic acid

ACTION AND USES

Folic acid is used in treatment of megaloblastic anemias that are caused by deficiency of folic acid. Although not related to anemia, studies indicate there is a decreased risk for neural tube defects if folic acid is taken before conception and during early pregnancy. Neural tube defects occur during early pregnancy, when the embryonic folds forming spinal cord and brain join together. Defects of this type include anencephaly, spina bifida, and meningocele.

Few adverse reactions are associated with administration of folic acid. Rarely, parenteral administration may result in allergic hypersensitivity.

CONTRAINDICATIONS, PRECAUTIONS, AND INTERACTIONS

a.       Folic acid is contraindicated for treatment of pernicious anemia or for other anemias for which vitamin B12 is deficient.

b.      Folic acid is considered safe for use during pregnancy. Pregnant women are more likely to experience folate acid deficiency because folic acid requirements are increased during pregnancy. Pregnant women with folate deficiency are at increased risk for complications of pregnancy and fetal abnormalities.

c.       Use of aminosalicylic with folic acid may decrease serum folate levels.

d.      Folic acid utilization is decreased when folate is administered with methotrexate.

e.       Signs of folic acid deficiency may occur when sulfasalazine is administered concurrently.

f.       An increase in seizure activity may occur when folic acid is administered with hydantoins.

Vitamin B12

Vitamin B12 is essential to growth, cell reproduction, the manufacture of myelin, and blood cell manufacture. The intrinsic factor, which is produced by cells in stomach, is necessary for absorption of vitamin B12 in the intestine. A deficiency of intrinsic factor results in abnormal formation of erythrocytes because of body’s failure to absorb vitamin

B12, a necessary component for blood cell formation. The resulting anemia is a type of megaloblastic anemia called pernicious anemia.

ACTIONS AND USES

Vitamin B12 (cyanocobalamin) is used to treat a vitamin B12 deficiency. A vitamin B12 deficiency may be seen in:

• Strict vegetarians

• Persons who have had a total gastrectomy or subtotal gastric resection.

• Persons who have intestinal diseases, such as ulcerative colitis or sprue

• Persons who have gastric carcinoma

• Persons who have a congenital decrease in number of gastric cells secreting intrinsic factor

Vitamin B12 is also used to perform Schilling test, which is used to diagnose pernicious anemia. A deficiency of this vitamin caused by low dietary intake of vitamin B12 is rare because vitamin is found in meats, milk, eggs, and cheese. The body is also able to store this vitamin; a deficiency, for any reason, will not occur for 5 to 6 years.

ADVERSE REACTIONS

Mild diarrhea and itching have been reported with administration of vitamin B12. Other adverse reactions that may be seen include a marked increase in RBC production, acne, peripheral vascular thrombosis, congestive heart failure, and pulmonary edema.

CONTRAINDICATIONS, PRECAUTIONS, AND INTERACTIONS

Vitamin B12 is contraindicated in patients allergic to cobalt. Vitamin B12 is administered cautiously during pregnancy and in patients with pulmonary disease and anemia. Alcohol, aminosalicylic acid, neomycin, and colchicine may decrease the absorption of oral vitamin B12.

Haemopoietics

The hematopoietic growth factors are glycoprotein hormones that regulate proliferation and differentiation of hematopoietic progenitor cells in bone marrow. The first growth factors to be identified were called colony-stimulating factors because they could stimulate growth of colonies of various bone marrow progenitor cells in vitro. Quantities of these growth factors sufficient for clinical use are produced by recombinant DNA technology.

Ex: erythropoietin, granulocyte colonystimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin 11.

The hematopoietic growth factors have complex effects on function of variety of cell types, including non-hematologic cells, anticancer and anti-inflammatory drugs.

Aspirin as anti platelet agents

The formation of platelet aggregates and thrombi in arterialblood may precipitate coronary vasospasm andocclusion, myocardial infarction, and stroke and contributeto atherosclerotic plaque development. Drugsthat inhibit platelet function are administered for specific prophylaxis of arterial thrombosis andfor the prophylaxis and therapeutic management ofmyocardial infarction and stroke.

a.       Aspirin inhibits platelet aggregation and prolongs bleeding time. It is useful for preventing coronary thrombosis in patients with unstable angina, as an adjunct to thrombolytic therapy, and in reducing recurrence of thrombotic stroke.

b.      It acetylates and irreversibly inhibits cyclooxygenase (primarily cyclooxygenase-1) both in platelets, preventing the formation of TxA2, and in endothelial cells, inhibiting synthesis of PGI2. While endothelial cells can synthesize cyclooxygenase, platelets cannot.

c.       The goal of therapy with aspirin is to selectively inhibit the synthesis of platelet TxA2 and thereby inhibit platelet aggregation.

d.      This is accomplished with a low dose of aspirin (160 to 325 mg per day), which spares the endothelial synthesis of PGI2.

e.       If ibuprofen is taken concurrently, it will bind reversibly to cyclooxygenase and prevent access of aspirin to its acetylation site and thus antagonize the ability of aspirin to inhibit platelets.

Anti-platelet agents

Classification

a.       Prostacycline PGI₂

b.      Inhibitors of TXA₂ formation: aspirin

c.       ADP receptor antagonists: ticlopidine, clopidogrel

d.      Phosphodiesterase inhibitors: dipyridamole

e.       Glycoprotein IIb/IIIa antagonists