Assignment -1

1.Drugs used for coagulation disorder

2.Drugs used for leukemia and lymphoma
Group-1 Assignment
Drugs forCoagulation Disorders
The drugs used in clotting and bleeding disorders fall
into 2 major groups:
(1) Anticlotting drugs used to decrease clotting or
dissolve clots already present in patients at risk for vascular occmyocardial

(2) Drugs that facilitate clotting used to increase clotting in

patients with clotting defiischemic

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 Anticlotting Drugs
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). Within the
anticlotting group, the anticoagulant and
thrombolytic drugs are effective in treatment of both
venous and arterial thrombosis,
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 Anticoagulant

Anticlottin Thrombolytics
g Drugs

Antiplatelet
Drugs
Classification

1.Anticoagulants inhibit the formation of fibrin clots. Three

major types of anticoagulants are available:

# Heparin and related products,

# Direct thrombin and factor X inhibitors,

# The orally active coumarin derivatives (eg, warfarin).

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heparin and related products,

which must be used parenterally

Chemistry
Heparin is a large sulfated polysaccharide polymer obtained from animal
sources. Each batch contains molecules of varying size, with an average
molecular weight of 15,000–20,000. Heparin is highly acidic and can be
neutralized by basic molecules (eg, protamine). Heparin is given
intravenously or subcutaneously 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. LMW heparins have greater bioavailability
and longer durations of action than unfractionated heparin; thus, doses can
be given less frequently (eg, once or twice a day). They are given
subcutaneously. Fondaparinux is a small synthetic drug that contains the
biologically active pentasaccharide present in unfractionated and LMW
heparins. It is administered subcutaneously once daily.

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heparin and related products,
Chemistry
large sulfated polysaccharide polymer
average molecular weight of 15,000–20,000.
highly acidic
• is given intravenously or subcutaneously
Mechanism and Effects

Unfractionated heparin binds to endogenous antithrombin III

(ATIII) via a key pentasaccharide sequence. The heparin–ATIII
complex combines with and irreversibly inactivates thrombin and
several other factors, particularly factor Xa (Figure).
In the presence of heparin, ATIII proteolyzes 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.

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Clinical Use
Because of its rapid effect, heparin is used when
anticoagulation is needed immediately (eg, when
starting therapy). Common uses include treatment of
DVT, pulmonary embolism, and acute myocardial
infarction. Heparin is used in combination with
thrombolytics for revascularization and in
combination with glycoprotein IIb/IIIa inhibitors
during angioplasty and placement of coronary stents.
Because it does not cross the placental barrier,
heparin is the drug of choice when an anticoagulant
must be used in pregnancy. LMW heparins and
fondaparinux have similar clinical applications.
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Toxicity(Adverse effect )
Increased bleeding is the most common adverse effect of
heparin and related molecules; the bleeding 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 in many
patients and severe thrombocytopenia and thrombosis
(heparin-induced thrombocytopenia or HIT) in a small
percentage 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. Prolonged use of unfractionated heparin is
associated with osteoporosis.
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Direct Thrombin Inhibitors
which are used parenterally or orally

Chemistry and Pharmacokinetics

Direct thrombin inhibitors are based on proteins made by Hirudo
medicinalis, the medicinal leech. 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. All 4 drugs
are administered parenterally. Dabigatran is an orally active direct
thrombin inhibitor.

Mechanism and Effects

The protein analogs of lepirudin bind simultaneously to the active site of
thrombin and to thrombin substrates. Argatroban binds solely to the
thrombin-active site. Unlike the heparins, these drugs inhibit both soluble
thrombin and the thrombin enmeshed within developing clots. Bivalirudin
also inhibits platelet activation.
Clinical Use
Direct thrombin inhibitors are used as alternatives to
heparin primarily in patients with heparin-induced
thrombocytopenia. Bivalirudin also is used in
combination with aspirin during percutaneous coronary
angioplasty. Like unfractionated heparin, the action of
these drugs is monitored with the aPTT laboratory test.

Toxicity
Like other anticoagulants, the direct thrombin
inhibitors can cause bleeding. No reversal agents exist.
Prolonged infusion of lepirudin can induce antibodies
that form a complex with lepirudin and prolong its
action, and it can induce anaphylactic reactions.
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Direct Oral Factor Xa Inhibitors
which are used parenterally or oralOrl

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. These drugs are given as fixed oral doses
and do not require monitoring. They undergo cytochrome P450-dependent and cytochrome
P450-independent elimination.

Mechanism and Effects

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

Clinical Use
Rivaroxaban is approved for prevention of venous thromboembolism following hip or knee
surgery and for prevention of stroke in patients with atrial fibrillation.

Toxicity
Like other anticoagulants, the factor Xa inhibitors can cause bleeding. No reversal agents
exist.

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Warfarin and Other Coumarin
Anticoagulants

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.

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. The vitamin K-
dependent factors include thrombin and factors VII, IX, and X (Figure 34–1). 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.
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Clinical Use
Warfarin is used for chronic anticoagulation in all of the clinical situations described previously for heparin,
except in pregnant women.

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.

Because warfarin has a narrow therapeutic window, its involvement in drug

interactions is of major concern. Cytochrome P450-inducing drugs (eg,
carbamazepine, phenytoin, rifampin, barbiturates) increase warfarin's clearance
and reduce the anticoagulant effect of a given dose. Cytochrome P450 inhibitors
(eg, amiodarone, selective serotonin reuptake inhibitors, cimetidine) reduce
warfarin's clearance and increase the anticoagulant effect of a given dose. Genetic
variability in cytochrome P450 2C9 and VKOR affect responses to warfarin.
Algorithms to determine initial warfarin dose based on cytochrome P450 2C9 and
VKOR, age, body size, and concomitant medications are being tested.
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Procoagulants(clotting Drugs )

The use of adsorbent chemicals, such as zeolites, and

other hemostatic agents are also used for sealing
severe injuries quickly (such as in traumatic bleeding
secondary to gunshot wounds). Thrombin and fibrin
glue are used surgically to treat bleeding and to
thrombose aneurysms.

Desmopressin is used to improve platelet function by

activating arginine vasopressin receptor 1A.


Coagulation factor concentrates are used to treat
hemophilia, to reverse the effects of anticoagulants, and to
treat bleeding in patients with impaired coagulation factor
synthesis or increased consumption.
Prothrombin complex concentrate, cryoprecipitate and
fresh frozen plasma are commonly used coagulation factor
products. Recombinant activated human factor VII is
increasingly popular in the treatment of major bleeding.

• Tranexamic acid and aminocaproic acid inhibit fibrinolysis,

and lead to a de facto reduced bleeding rate. Before its
withdrawal, aprotinin was used in some forms of major
surgery to decrease bleeding risk and need for blood
products.