Download oral direct thrombin inhibitors

BLOOD COAGULATION
As I explained in the previous lecture at Fig 7 that local stimulation of the coagulation cascade
(coagulation factors) by tissue mediators released from the injured tissue, convert prothrombin (
factor II) which is inactive into thrombin (factor IIa) which is active. ; thrombin is coagulation factor
that convert fibrinogen ( {weak, soluble} into fibrin (strong, insoluble) which is incorporated into the
plug. Subsequent cross-linking of the fibrin strands stabilizes the clot and forms a hemostatic plateletfibrin plug . From this information , anticoagulant drugs act via one of the following targets:
1- Against coagulation factors: The vitamin K antagonists such as warfarin
2- Against thrombin (factor IIa) : The thrombin inhibitors, such as heparin and heparin-related agents
3- Against fibrin : The fibrinolytics
1-The vitamin K antagonists: Warfarin
1. Mechanism of action:
Several of the protein coagulation factors (including Factors II, VII, IX, and X) require vitamin K as a
cofactor for their activation. These factors undergo vitamin K–dependent modification, whereby a number of
their glutamic acid residues are carboxylated to form ɤ-carboxyglutamic acid residues (Figure). The ɤ carboxyglutamyl residues bind calcium ions, which are essential for interaction between the coagulation
factors and platelet membranes. In the carboxylation reactions, the vitamin K–dependent carboxylase fixes
CO2 to form the new COOH group on glutamic acid. The reduced vitamin K cofactor is converted to vitamin
K epoxide during the reaction. Vitamin K is regenerated from the epoxide by vitamin K epoxide reductase,
the enzyme that is inhibited by warfarin. Warfarin treatment results in the production of clotting factors with
diminished activity (10%–40% of normal), due to the lack of sufficient ɤ-carboxyglutamyl side chains. The
anticoagulant effects of warfarin are not observed until 8 to 12 hours after drug administration, but peak
effects may be delayed for 72 to 96 hours (the time required to deplete the pool of circulating clotting
factors).
2. Therapeutic uses: Warfarin is used to prevent the progression or recurrence of acute deep vein thrombosis
or pulmonary embolism after initial heparin treatment.. Prophylactically, it is used in patients with acute
myocardial infarction, prosthetic heart valves, and chronic atrial fibrillation.
3. Pharmacokinetics:
a. Absorption: Warfarin is rapidly absorbed after oral administration (100% bioavailability with little
individual patient variation). Warfarin is 99 percent bound to plasma albumin, which prevents its diffusion
into the cerebrospinal fluid, urine, and breast milk. However, drugs that have a greater affinity for the
albumin-binding site, such as sulfonamides, can displace the anticoagulant and lead to a transient, elevated
activity (Drugs that affect warfarin binding to its plasma proteins can lead to drug interactions and variability
in the therapeutic response to warfarin).
*Warfarin readily crosses the placental barrier.
*The mean half-life of warfarin is approximately 40 hours.
*Warfarin has a narrow therapeutic index. INR values below or above the range increase the risk of
thrombosis and bleeding, respectively.
b. Fate: The products of warfarin metabolism, catalyzed by the CYP450 system, are inactive. After
conjugation to glucuronic acid, they are excreted in urine and feces. Agents that affect the metabolism of
warfarin may alter its therapeutic effects.
4. Adverse effects:
a. Bleeding disorders: The principal unwanted reaction caused by warfarin treatment is hemorrhage.
Therefore, it is important to frequently monitor and adjust the anticoagulant effect. Minor bleeding may
be treated by withdrawal of the drug and administration of oral vitamin K1, but severe bleeding requires that
greater doses of the vitamin be given intravenously. Skin lesions and necrosis are rare complications of
warfarin therapy and are observed primarily in women.
b. Drug interactions: Warfarin has numerous drug interactions that may potentiate or attenuate its
anticoagulant effect. The list of interacting drugs is extensive. A summary of some of the important
interactions is shown in the Figure.
c. Contraindications: Warfarin should never be used during pregnancy, because it is teratogenic and can
cause abortion as well as birth defects (FDA pregnancy category X). If anticoagulant therapy is needed during
pregnancy, heparin or LMWH may be administered.
Monitoring of effect: by international normalized ratio (INR). The INR is the prothrombin time ratio (patient
prothrombin time/mean of normal prothrombin time for lab). The recommended INR for prophylaxis and
treatment of thrombotic disease is 2–3. Patients with some types of artificial heart valves or other medical
conditions increasing thrombotic risk have a recommended range of 2.5–3.5.
2-Thrombin inhibitors:
I- Indirect thrombin inhibitors:
@Parentral preparations:
A- Unfractionated heparin (Heparin):
Unfractionated heparin is an injectable (I.v. or deep S/c) , rapidly acting anticoagulant that is often used
acutely to interfere with the formation of thrombi. it is a mixture of straight-chain, anionic
glycosaminoglycans with a wide range of molecular weights (3000-30000). {I.M use is contraindicated due
to heamatoma}.
Mechanism of action:
In the absence of heparin, antithrombin III interacts very slowly with thrombin and Factor Xa. Heparin
molecules bind to antithrombin III, inducing a conformational change that accelerates its rate of action about
1000-fold. So Heparin serves as a true catalyst, allowing antithrombin III to rapidly combine with and inhibit
circulating thrombin and Factor Xa.
Discriptions of UFH:
@- Consists of a family of molecules of different molecular weights (5000–30,000) extracted from porcine
intestinal mucosa and bovine lung. Only about a third of these have an accelerating effect because the
remainder lack the unique pentasaccharide sequence needed. So the correlation between the concentration of
a given UF Heparin and its effect on coagulation often is poor
@- UF Heparin contain contaminants; this linked to high adverse events in patients, most commonly
hypotension, nausea, and dyspnea within 30 minutes of infusion.
@ Close monitoring of the activated partial thromboplastin time (aPTT or PTT ) is necessary in patients
receiving UFH. Levels of UFH may also be determined by protamine titration (therapeutic levels 0.2–0.4
unit/mL) or anti-Xa units (therapeutic levels 0.3–0.7 unit/mL).
B- Low molecular weight heparins (LMWHs): such as enoxaparin, dalteparin, and tinzaparin. These are
products produced by different manufacturers sharing the unique pentasaccharide sequence contained in the
unfractionated heparin.
Mechanism of action:
In contrast to the unfractionated heparin , LMWHs complex with antithrombin III (via pentasaccharide
sequence) and inactivate Factor Xa but do not or with little bind to thrombin.
Discriptions :
@increased bioavailability from the subcutaneous site of injection,
@ less frequent dosing requirements (once or twice daily is sufficient).
@Monitoring of Effect: Weight-based dosing of the LMW heparins results in predictable pharmacokinetics
and plasma levels in patients with normal renal function. Therefore, LMW heparin levels are not generally
measured except in the setting of renal insufficiency and pregnancy. LMW heparin levels can be determined
by anti-Xa units. Peak therapeutic levels should be 0.5–1 unit/mL for twice-daily dosing, determined 4 hours
after administration, and approximately 1.5 units/mL for once-daily dosing.
Toxicity of UFH and LMW heparin
A. Bleeding : The major adverse effect of heparin is bleeding. This risk can be decreased by careful control of
dosage and close monitoring. Elderly women and patients with renal failure are more prone to hemorrhage.
B. Heparin is of animal origin and should be used cautiously in patients with allergy.
C. Increased loss of hair and reversible alopecia have been reported.
D. Long-term heparin therapy is associated with osteoporosis and spontaneous fractures.
E. Longterm use is associated with mineralocorticoid deficiency.
F- Heparin-Induced Thrombocytopenia
Heparin-induced thrombocytopenia (HIT) is immune response to heparin occurs in 1–4% of individuals
treated with UFH for a minimum of 7 days. Patients who develop HIT are treated by discontinuance of
heparin and administration of a direct thrombin inhibitor.
@Oral preparations: Rivaroxaban, Apixaban
These drugs inhibit factor Xa, in the final common pathway of clotting . These drugs are given as fixed doses
and do not require monitoring. They have a rapid onset of action and shorter half-lives than warfarin
(approximately 10 hours but half-life may be prolonged in elderly patients or those with renal impairment).
Rivaroxaban is approved for prevention of venous thromboembolism following hip or knee surgery. The
prophylactic dose is 10 mg orally per day.
Apixaban is currently in clinical development.
Both of these drugs are excreted in part by the kidneys; therefore, the dosage may need to be reduced in
patients with renal impairment. In such patients, use of a hepatically metabolized drug such as warfarin may
be a better alternative.
II-DIRECT THROMBIN INHIBITORS
@PARENTERAL DIRECT THROMBIN INHIBITORS: Lepirudin, Bivalirudin, Argatroban
Lepirudin is a specific, irreversible thrombin inhibitor . Its action is independent of antithrombin, which
means it can reach and inactivate fibrin-bound thrombin in thrombi. Lepirudin has little effect on platelets or
the bleeding time. Lepirudin is approved by the FDA for use in patients with thrombosis related to heparininduced thrombocytopenia. Lepirudin is excreted by the kidney and should be used with great caution in
patients with renal insufficiency.
Bivalirudin, another 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.
Bivalirudin also inhibits platelet activation and has been FDA-approved for use in percutaneous coronary
angioplasty.
Argatroban is a small molecule thrombin inhibitor that is FDA-approved for use in patients with HIT with or
without thrombosis and coronary angioplasty in patients with HIT. It, too, has a short half-life, is given by
continuous intravenous infusion. Its clearance is not affected by renal disease but is dependent on liver
function; dose reduction is required in patients with liver disease.
@ORAL DIRECT THROMBIN INHIBITORS: Dabigatran
Advantages of oral direct thrombin inhibitors in comparison with warfarin :
- More Predictable pharmacokinetics and bioavailability, which allow for fixed dosing and predictable
anticoagulant response, and make routine coagulation monitoring unnecessary.
-Their rapid onset and offset of action allow for immediate anticoagulation, thus avoiding the need for
overlap with additional anticoagulant drugs (As with heparin and warfarin)
Dabigatran is the first oral direct thrombin inhibitor approved by the FDA. Dabigatran at a dose of 150 mg
b.i.d was shown to be superior to warfarin with an INR target of 2–3 in preventing stroke and systemic
embolization. Concomitant use of ketoconazole, amiodarone, quinidine, and clopidogrel increases the effect
of dabigatran. The half-life of the drug is 12–17 hours. Renal impairment results in prolonged drug clearance
and may require dose adjustment.
Toxicity
As with any anticoagulant drug, the primary toxicity of dabigatran is bleeding such as gastrointestinal
bleeding.
3- The Fibrinolytics:
(Note fig 8 in the previous section).
Fibrinolytic drugs rapidly lyse thrombi by catalyzing the formation
of plasmin from its precursor
plasminogen. Plasmin formed inside a thrombus by these activators lyse the thrombus.
These drugs create a generalized lytic state when administered intravenously. Thus, both protective
hemostatic thrombi and target thromboemboli are broken down.
Streptokinase is a protein synthesized by streptococci that combines with the proactivator plasminogen. This
enzymatic complex catalyzes the conversion of inactive plasminogen to active plasmin.
Urokinase is a human enzyme synthesized by the kidney that directly converts plasminogen to active
plasmin.
Anistreplase consists of a complex of purified human plasminogen and bacterial streptokinase. When
administered. This product (now discontinued in the USA)
alteplase is a tissue plasminogen activators (t-PAs). These activators preferentially activate plasminogen
that is bound to fibrin, which (in theory) confines fibrinolysis to the formed thrombus and avoids systemic
activation. alteplase is manufactured by means of recombinant DNA technology.
Indications:
Administration of fibrinolytic drugs by the intravenous route is
indicated in cases of Acute myocardial infarction (acute coronary occlusion by a thrombus), pulmonary
embolism with hemodynamic instability, severe deep venous thrombosis such as the superior vena caval
syndrome
Adverse effects:
-Bleeding
-Patients with antistreptococcal antibodies can develop fever, allergic reactions, and therapeutic resistance
with streptokinase and Anistreplase.
*A single course of fibrinolytic drugs is expensive: hundreds of dollars for streptokinase and thousands for
urokinase and t-PA.
* All trials to date show the greatest benefit for thrombolytic therapy when it is given early, within
6 hours after symptomatic onset of acute myocardial infarction. i.e. they act better before thrombus aging.