DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

866 Dabigatran etexilate is approved in the E.U. and Canada for prevention
of venous thromboembolism after elective hip or knee replacement
surgery. It is not yet available in the U.S. In phase III trials,
dabigatran etexilate was non-inferior to warfarin for treatment of
patients with venous thromboembolism (Schulman et al., 2009) and
superior to warfarin for stroke prevention in patients with atrial fibrillation
(Connolly et al., 2009). Therefore, this drug represents a
promising alternative to warfarin for patients who require long-term
anticoagulation.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Rivaroxaban (XARELTO). An oral factor Xa inhibitor,
rivaroxaban has 80% oral bioavailability, a peak onset of
action in 3 hours, and a plasma t 1/2
of 7-11 hours.
About one-third of the drug is excreted unchanged in the urine,
the remainder is metabolized by the liver, and inactive metabolites are
excreted in the urine or feces. This drug is given in fixed doses and
does not require coagulation monitoring. Like dabigatran etexilate,
rivaroxaban also is approved in the E.U. and Canada for thromboprophylaxis
after hip or knee replacement surgery. Rivaroxaban is not
available in the U.S. Ongoing trials are comparing rivaroxaban with
warfarin for treatment of venous thromboembolism and stroke prevention
in patients with atrial fibrillation.
Other New Agents. Other new oral anticoagulants include apixaban,
edoxaban, betrixaban, YM150, and TAK-442, which are oral factor
Xa inhibitors, and AZD0837, which is an oral thrombin inhibitor.
Apixaban and edoxaban are currently undergoing phase III clinical
evaluation.
FIBRINOLYTIC DRUGS
The fibrinolytic pathway is summarized by Figure 30–3.
The action of fibrinolytic agents is best understood in
conjunction with an understanding of the characteristics
of the physiological components.
Plasminogen. Plasminogen is a single-chain glycoprotein
of 791 amino acids; it is converted to an active protease
by cleavage at Arg 560 .
Plasminogen’s five kringle domains mediate the binding of
plasminogen (or plasmin) to carboxyl-terminal lysine residues in partially
degraded fibrin; this enhances fibrinolysis. A plasma carboxypeptidase
termed thrombin-activatable fibrinolysis inhibitor
(TAFI) can remove these lysine residues and thereby attenuate fibrinolysis.
The lysine binding kringle domains of plasminogen are
located between amino acids 80 and 165, and they also promote
formation of complexes of plasmin with α 2
-antiplasmin, the major
physiological plasmin inhibitor. Plasminogen concentrations in
human plasma average 2 μM. A plasmin-degraded form of plasminogen
termed lys-plasminogen binds to fibrin with higher affinity
than intact plasminogen.
α 2
-Antiplasmin. α 2
-Antiplasmin, a glycoprotein of 452
amino acid residues, forms a stable complex with plasmin,
thereby inactivating it.
Plasma concentrations of α 2
-antiplasmin (1 μM) are sufficient
to inhibit about 50% of potential plasmin. When massive activation
of plasminogen occurs, the inhibitor is depleted, and free plasmin
causes a “systemic lytic state” in which hemostasis is impaired. In
this state, fibrinogen is degraded and fibrinogen degradation products
impair fibrin polymerization and therefore increase bleeding
from wounds. α 2
-Antiplasmin inactivates plasmin nearly instantaneously,
as long as the first kringle domain on plasmin is unoccupied
by fibrin or other antagonists, such as aminocaproic acid (see
“Inhibitors of Fibrinolysis” section).
Streptokinase. Streptokinase (STREPTASE) is a 47,000-Da
protein produced by β-hemolytic streptococci. It has no
intrinsic enzymatic activity but forms a stable, noncovalent
1:1 complex with plasminogen. This produces a
conformational change that exposes the active site on
plasminogen that cleaves Arg 560 on free plasminogen to
form plasmin.
Since the advent of newer agents, streptokinase is rarely used
clinically for fibrinolysis. It currently is not marketed in the U.S.
Tissue Plasminogen Activator. t-PA is a serine protease
of 527 amino acid residues. It is a poor plasminogen activator
in the absence of fibrin (Lijnen and Collen, 2001).
t-PA binds to fibrin via its finger domain and second
lysine-binding kringle domain and activates fibrin-bound
plasminogen several hundredfold more rapidly than it
activates plasminogen in the circulation. The finger
domain is homologous to a similar site on fibronectin,
whereas the lysine binding kringle domain is homologous
to the kringle domains on plasminogen.
Because it has little activity except in the presence of fibrin,
physiological t-PA concentrations of 5-10 ng/mL do not induce systemic
plasmin generation. During therapeutic infusions of t-PA, however,
when concentrations rise to 300-3000 ng/mL, a systemic lytic
state can occur. Clearance of t-PA primarily occurs by hepatic metabolism,
and its t 1/2
is ~5 min. t-PA is effective in lysing thrombi during
treatment of acute myocardial infarction or acute ischemic stroke.
t-PA (alteplase, ACTIVASE) is produced by recombinant DNA
technology. The currently recommended (“accelerated”) regimen for
coronary thrombolysis is a 15-mg intravenous bolus, followed by
0.75 mg/kg of body weight over 30 minutes (not to exceed 50 mg)
and 0.5 mg/kg (up to 35 mg accumulated dose) over the following
hour. Recombinant variants of t-PA now are available (reteplase,
RETAVASE and tenecteplase, TNKASE). They differ from native t-PA
by having longer plasma half-lives that allow convenient bolus
dosing; reteplase is administered in two bolus doses given 30 minutes
apart, while tenecteplase requires only a single bolus. In contrast
to t-PA and reteplase, tenecteplase is relatively resistant to
inhibition by PAI-1. Despite these apparent advantages, these
agents are similar to t-PA in efficacy and toxicity (GUSTO III
Investigators, 1997).
Hemorrhagic Toxicity of Thrombolytic Therapy. The
major toxicity of all thrombolytic agents is hemorrhage,