This document discusses the mechanisms of action, side effects, and clinical management of anticoagulant drugs including heparin, warfarin, and newer oral anticoagulants. It describes how heparin and related drugs act as indirect thrombin inhibitors by enhancing the effects of antithrombin, while direct thrombin inhibitors and factor Xa inhibitors act by directly binding to and inhibiting specific coagulation proteins. The side effects of bleeding and heparin-induced thrombocytopenia are reviewed for heparin, as are methods for reversing its effects. Drug interactions and toxicity are discussed for warfarin along with reversal of its anticoagulant effects.

1. Basic pharmacology of
the anticoagulant drugs
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2. Learning objectives
 To discuss the mechanisms of action of anticoagulants
 To describe the side effects of heparin
 To discuss the clinical management of heparin toxicity
 To list the common adverse effects of warfarin
 To discuss the drug interactions of warfarin
 To describe the clinical management of warfarin toxicity
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3. Introduction
 The ideal anticoagulant drug would prevent pathologic
thrombosis but allow a normal response to vascular injury
and limit bleeding
 This could be accomplished by preservation of the TF-VIIa
initiation phase of the clotting mechanism
 Practically , such a drug does not exist;
 All anticoagulants have an increased bleeding risk
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4. Indirect thrombin inhibitors
 Antithrombotic effect is exerted by their interaction with a
separate protein, antithrombin
Unfractionated heparin (UFH)
 lowmolecular-weight heparin (LMWH)
Fondaparinux
 Bind to antithrombin and enhance inhibition of clotting factor
proteases
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5. Heparin
 Chemistry & Mechanism of Action
 A heterogeneous mixture of sulfated mucopolysaccharides
 Its biologic activity is dependent upon the endogenous
anticoagulant antithrombin
 Antithrombin inhibits clotting factor proteases, especially thrombin
(IIa), IXa, and Xa, by forming stable complexes with them
 In the absence of heparin, these reactions are slow; in the
presence of heparin, they are accelerated 1000-fold
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6. Cont..
 The active heparin molecules bind tightly to
antithrombin and cause a conformational change in
this inhibitor
 The conformational change of antithrombin exposes
its active site for more rapid interaction with the
proteases (the activated clotting factors)
 Heparin functions as a cofactor for the antithrombin-
protease reaction without being consumed
 Once the antithrombin-protease complex is formed,
heparin is released intact for renewed binding to more
antithrombin
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7. Cont..
 High-molecular-weight (HMW), also known as UFH
 HMW : fractions of heparin with high affinity for antithrombin
 low-molecular-weight (LMW) fractions of heparin have less effect on
thrombin than the HMW species
 LMW heparins such as enoxaparin, dalteparin, and tinzaparin
 LMWHS are effective in several thromboembolic conditions
 LMW heparins—in comparison with UFH
 equal efficacy
 increased bioavailability from the subcutaneous site of injection
 less frequent dosing requirements (once or twice daily is sufficient)
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8. Toxicity
A. Bleeding and miscellaneous effects
 The major adverse effect of heparin is bleeding
 Elderly women and patients with renal failure are more prone to
hemorrhage
 Heparin is of animal origin and should be used cautiously in
patients with allergy
 Increased loss of hair and reversible alopecia have been
reported
 Long-term heparin therapy is associated with osteoporosis and
spontaneous fractures
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9. B. Heparin-induced thrombocytopenia
 (HIT) is a systemic hypercoagulable state that occurs in 1–
4% of individuals treated with UFH for a minimum of 7 days
 Surgical patients are at greatest risk
 The risk of HIT may be higher in individuals treated with
UFH of bovine origin and is lower in those treated with
LMWH
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10. Reversal of heparin action
 If bleeding occurs, administration of a specific antagonist such as
protamine sulfate is indicated
 Protamine is a highly basic, positively charged peptide that combines
with negatively charged heparin as an ion pair to form a stable complex
devoid of anticoagulant activity
 For every 100 units of heparin remaining in the patient, 1 mg of
protamine sulfate is given intravenously
 the rate of infusion should not exceed 50 mg in any 10-minute period
 Excess protamine must be avoided; it also has an anticoagulant effect
 Neutralization of LMW heparin by protamine is incomplete
 1 mg of protamine sulfate may be used to partially neutralize 1 mg of
enoxaparin
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11. Contraindications
 HIT
 Hypersensitivity to the drug
 Active bleeding
 Hemophilia
 Severe hypertension
 Intracranial hemorrhage
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12. Direct thrombin inhibitors
 Exert their anticoagulant effect by directly binding to
the active site of thrombin
 Thereby inhibiting thrombin’s downstream effects
 Hirudin and bivalirudin are bivalent DTIs in that they
bind at both the catalytic or active site of thrombin as
well as at a substrate recognition site
 Argatroban and melagatran are small molecules that
bind only at the thrombin active site
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13. Cont.…
Hirudin
 A specific, irreversible thrombin inhibitor
 Now available in recombinant form as lepirudin
 it must be administered parenterally
 Lepirudin is approved by the FDA for use in patients with thrombosis
related to heparin-induced thrombocytopenia
 Lepirudin is excreted by the kidney and should be used with great
caution in patients with renal insufficiency
 No antidote exists
 Up to 40% of patients who receive long-term infusions develop an
antibody directed against the thrombin-lepirudin complex
 These antigen-antibody complexes are not cleared by the kidney and
may result in an enhanced anticoagulant effect
 Some patients re-exposed to the drug have developed life-threatening
anaphylactic reactions
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14. Bivalirudin
 Another bivalent inhibitor of thrombin
 Is administered intravenously
 With a rapid onset and offset of action
 The drug has a short half-life with clearance that is
20% renal and the remainder metabolic
 Also inhibits platelet activation and has been FDA-
approved for use in percutaneous coronary angioplasty
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15. Oral direct factor XA inhibitors
 Rivaroxaban and apixaban
 Inhibit factor Xa, in the final common pathway of clotting
 Approved in advanced stages of development and along with
oral thrombin inhibitors
 Given as fixed doses and do not require monitoring
 They have a rapid onset of action and shorter half-lives than
warfarin
 Half-life may be prolonged in elderly patients or those with renal
impairment
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16. Oral direct thrombin inhibitors
 Advantages of oral direct thrombin inhibitors
o Predictable pharmacokinetics and bioavailability, which
allow for fixed dosing and predictable anticoagulant
response
o Make routine coagulation monitoring unnecessary
 Dabigatran etexilate mesylate is the first oral direct
thrombin inhibitor approved by the FDA
 Dabigatran was approved in 2010 to reduce risk of
stroke and systemic embolism with atrial fibrillation
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17. Warfarin
 Pharmacokinetics
 In the 1950s warfarin (under the brand name Coumadin)
was introduced as an antithrombotic agent in humans
 Warfarin is generally administered as the sodium salt
 has 100% bioavailability
 Over 99% of racemic warfarin is bound to plasma albumin,
 Small volume of distribution (the albumin space)
 Long half-life in plasma (36 hours)
 The lack of urinary excretion of unchanged drug
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18.  A racemic mixture composed of equal amounts of
two enantiomorphs
 The levorotatory S-warfarin is four times more
potent than the dextrorotatory R-warfarin
 Stereoselective nature of several drug interactions
involving warfarin
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19. Mechanism of action
 Coumarin anticoagulants block the γ-carboxylation of several
glutamate residues in prothrombin and factors VII, IX, and X as well
as the endogenous anticoagulant proteins C and S
 The blockade results in incomplete coagulation factor molecules that
are biologically inactive
 The protein carboxylation reaction is coupled to the oxidation of
vitamin K. The vitamin must then be reduced to reactivate it
 Warfarin prevents reductive metabolism of the inactive vitamin K
epoxide back to its active hydroquinone form
 Mutational change of vitamin K epoxide reductase, can give rise to
genetic resistance to warfarin
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20. Toxicity
 warfarin should never be administered during pregnancy
 Crosses the placenta readily and can cause a hemorrhagic
disorder in the fetus
 The drug can cause a serious birth defect characterized by
abnormal bone formation
 Cutaneous necrosis with reduced activity of protein C
sometimes occurs during the first weeks of therapy
 The pathologic lesion associated with the hemorrhagic infarction
is venous thrombosis, suggesting that it is caused by warfarin-
induced depression of protein C synthesis
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21. Drug interactions
 Interactions can be broadly divided
 pharmacokinetic
 pharmacodynamic
 Pharmacokinetic mechanisms
 enzyme induction,
enzyme inhibition,
 reduced plasma protein binding
 Pharmacodynamic mechanisms
 synergism
 competitive antagonism
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22. Cont..
 The most dangerous of these interactions are the pharmacokinetic
interactions with the mostly obsolete pyrazolones phenylbutazone and
sulfinpyrazone
 These drugs not only augment the hypoprothrombinemia but also inhibit
platelet function and may induce peptic ulcer disease
 The mechanisms for their hypoprothrombinemic interaction are a
stereoselective inhibition of oxidative metabolic transformation of S-warfarin
and displacement of albumin- bound warfarin, increasing the free fraction
 Metronidazole, fluconazole, and trimethoprim-sulfamethoxazole also
stereoselectively inhibit the metabolic transformation of S -warfarin
 Amiodarone, disulfiram, and cimetidine inhibit metabolism of both
enantiomorphs of warfarin
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23.  Aspirin, hepatic disease, and hyperthyroidism
augment warfarin’s effect
 The third-generation cephalosporins eliminate the
bacteria in the intestinal tract that produce vitamin K
and, like warfarin, also directly inhibit vitamin K
epoxide reductase
 Barbiturates and rifampin cause a marked decrease of
the anticoagulant effect
 Cholestyramine reduces its absorption and
bioavailability
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24.  Pharmacodynamic reductions of anticoagulant effect occur
o with vitamin K (increased synthesis of clotting factors)
o the diuretics chlorthalidone and spironolactone (clotting factor
concentration)
o hypothyroidism (decreased turnover rate of clotting factors)
 Drugs with no significant effect on anticoagulant therapy include
o Ethanol
o Phenothiazines
o Benzodiazepines
o Acetaminophen
o Opioids
o indomethacin
o most antibiotics
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25. Reversal of warfarin action
 Excessive anticoagulant effect and bleeding can be reversed by
 stopping the drug and administering oral or parenteral vitamin K 1
(phytonadione), fresh-frozen plasma, prothrombin complex concentrates
such as Bebulin and Proplex T, and recombinant factor VIIa (rFVIIa)
 Excess of anticoagulant effect without bleeding may require no more
than cessation of the drug
 Important to note that due to the long half-life of warfarin, a single dose
of vitamin K or rFVIIa may not be sufficient
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