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

874 has received anticoagulant or anticonvulsant drug therapy or if the
infant develops bleeding tendencies. Alternatively, some clinicians
treat mothers who are receiving anticonvulsants with oral vitamin K
prior to delivery (20 mg/day for 2 weeks) (Vert and Deblay, 1982).
Inadequate Absorption. Vitamin K is poorly absorbed in the absence
of bile. Thus, hypoprothrombinemia may be associated with either
intrahepatic or extrahepatic biliary obstruction or a severe defect in
the intestinal absorption of fat from other causes.
Biliary Obstruction or Fistula. Bleeding that accompanies obstructive
jaundice or biliary fistula responds promptly to the administration
of vitamin K. Oral phytonadione administered with bile salts is
both safe and effective and should be used in the care of the jaundiced
patient, both preoperatively and postoperatively. In the absence
of significant hepatocellular disease, the prothrombin activity of the
blood rapidly returns to normal. If oral administration is not feasible,
a parenteral preparation should be used. The usual dose is 10 mg/day
of vitamin K.
The treatment of a patient during hemorrhage requires transfusion
of fresh blood or reconstituted fresh plasma. Vitamin K also
should be given. If biliary obstruction has caused hepatic injury, the
response to vitamin K may be poor.
Malabsorption Syndromes. Among the disorders that result in inadequate
absorption of vitamin K from the intestinal tract are cystic
fibrosis, sprue, Crohn’s disease and enterocolitis, ulcerative colitis,
dysentery, and extensive resection of bowel. Because drugs that
greatly reduce the bacterial population of the bowel are used frequently
in many of these disorders, the availability of the vitamin
may be further reduced. Moreover, dietary restrictions also may limit
the availability of the vitamin. For immediate correction of the deficiency,
parenteral therapy should be used.
Inadequate Utilization. Hepatocellular disease may be accompanied
or followed by hypoprothrombinemia. Hepatocellular damage
also may be secondary to long-lasting biliary obstruction. In these
conditions, the damaged parenchymal cells may not be able to produce
the vitamin K-dependent clotting factors, even if excess vitamin
is available. However, if an inadequate secretion of bile salts is
contributing to the syndrome, some benefit may be obtained from
the parenteral administration of 10 mg of phytonadione daily.
Paradoxically, the administration of large doses of vitamin K or its
analogs in an attempt to correct the hypoprothrombinemia associated
with severe hepatitis or cirrhosis actually may result in a further
depression of the concentration of prothrombin. The mechanism for
this action is unknown.
Drug- and Venom-Induced Hypoprothrombinemia. Anticoagulant drugs
such as warfarin and its congeners act as competitive antagonists
of vitamin K and interfere with the hepatic biosynthesis of Glacontaining
clotting factors. The treatment of bleeding caused by oral
anticoagulants is discussed earlier in this chapter. Vitamin K may be
of help in combating the bleeding and hypoprothrombinemia that
follow the bite of the tropical American pit viper or other species
whose venom destroys or inactivates prothrombin.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
CLINICAL SUMMARY
A variety of anticoagulant, fibrinolytic, and antiplatelet
agents are available and are among the most widely
used drugs. Heparin and LMWHs are commonly used
to treat venous thromboembolism, unstable angina,
and acute myocardial infarction; these agents also are
used to prevent thrombosis during coronary angioplasty
and for certain other high-risk indications. The
major toxicities of heparin are bleeding and the syndrome
of heparin-induced thrombocytopenia, which
often precipitates venous or arterial thrombosis. Direct
thrombin inhibitors, such as lepirudin, bivalirudin, and
argatroban, are indicated for patients with heparininduced
thrombocytopenia.
Warfarin and other vitamin K antagonists are used
to prevent the progression or recurrence of acute venous
thromboembolism following an initial course of heparin.
They also decrease the incidence of systemic embolization
in patients with atrial fibrillation or prosthetic heart
valves. Warfarin has a narrow therapeutic index drug
and is associated with more than 200 drug-drug and
drug-food interactions. Over- and under-dosing are associated
with serious consequences, including thrombosis
or major bleeding in a significant number of patients.
Warfarin also produces fetal abnormalities when given
during pregnancy. New oral anticoagulants that target
thrombin or factor Xa hopefully will replace warfarin in
the future. These drugs have the potential to streamline
care because they can be given in fixed doses without
coagulation monitoring.
Fibrinolytic agents, such as t-PA or its derivatives,
reduce the mortality of acute myocardial infarction and
are used in situations in which angioplasty is not readily
available. Fibrinolytic therapy also is used for
patients with acute ischemic stroke.
Antiplatelet agents, including aspirin, clopidogrel,
prasugrel, and glycoprotein IIb/IIIa inhibitors, are
used to prevent thrombosis after coronary angioplasty
and in the secondary prevention of myocardial infarction
and stroke. Bleeding is the major toxicity of the
antiplatelet agents. Newer antiplatelet drugs that directly
target the ADP or thrombin receptor on platelets are in
advanced stages of development. These more potent
antiplatelet drugs may produce more bleeding, highlighting
the inevitable link between the efficacy and toxicity
of anti-thrombotic drugs.
BIBLIOGRAPHY
Almquist HJ, Stokstad CLR. Hemorrhagic chick disease of
dietary origin. J Biol Chem, 1935, 111:105–113.
Andersen HR, Nielsen TT, Rasmussen K, et al. DANAMI-2
Investigators. A comparison of coronary angioplasty with fibrinolytic
therapy in acute myocardial infarction. N Engl J Med,
2003, 349:733–742.