Sesión de Carteles
M. C. Ernestina Hernández
Aspirin Prophylaxis of myocardial infarction Prophylaxis of stroke Analgesic Antipyretic Antiinflammatory Bleeding Tinnitus Respiratory alkalosis followed by metabolic acidosis in overdose Hypersensitivity Bleeding disorders In children (<16 years of age) for viral infections Pregnancy (especially 3rd trimester)
Mechanism: Platelet ADP antagonist
Clopidogrel Ticlopidine
Reduces atherothrombotic events (myocardial infarction, stroke, vascular deaths)
Treat unstable angina and non- ST-segment elevation myocardial infarction
Patients with stents
Ticlopidine should be reserved for patients who are intolerant to aspirin
Cutaneous
Gastrointestinal problems Hematologic (all worse with ticlopidine) Hypersensitivity Pathological bleeding; peptic ulcers or intracranial hemorrhage Coagulation disorders
Mechanism: Inhibits phosphodiesterase and increases cAMP; decreases platelet aggregation and vasodilate
Dipyridamole
Used with warfarin to decrease thrombosis after artificial heart valve replacement
Diagnostic in coronary artery disease
Hypotension Rash
Hypersensitivity
Mechanism: Binds to the glycoprotein receptors IIb and IIIa on activated platelets; inhibits platelet aggregation
Abciximab Eptifibatide Tirofiban
Percutaneous coronary intervention
Hypotension Bleeding
Hypersensitivity Bleeding disorders
Mechanism: Inhibitor of phosphodiesterase III; thus, increasing cAMP leading to inhibition of platelet aggregation,
vasodilation, and inhibition of vascular smooth muscle cell proliferation Cilostazol
Intermittent claudication Peripheral vascular disease
Bleeding Hypotension Hypersensitivity Bleeding disorders Heart failure
194 / 445
Mechanism: Inhibits megakaryocyte development in late postmitotic stage
Anagrelide Treat thrombocythemia associated with
myeloproliferative disorders Palpitations Headache Thrombocytopenia
Hepatic disease
cAMP, cyclic adenosine monophosphate. BOX 16-2 ANTICOAGULANTS Heparin-Related Compounds Fondaparinux Heparin (UFH) Low-molecular-weight heparins (LMWHs) Dalteparin Enoxaparin Nadroparin Tinzaparin
Direct Thrombin Inhibitors
The -rudins: hirudin, bivalirudin, lepirudin Argatroban
Oral Anticoagulant
Warfarin
Table 16-3. Comparison Between Unfractionated Heparin and Low-Molecular-Weight Heparins
PROPERTY HEPARIN LMWH
Anti-Xa versus anti-IIa activity 1:1 2:1-4:1
PTT monitoring Required Not required
Inhibition of platelet function ++++ ++
Endothelial cell protein binding Extensive Minimal
Dose-dependent clearance Yes No
Elimination half-life Short (50-90 minutes) Long (2-5 times longer)
LMWH, low-molecular-weight heparin; PTT, partial thromboplastin time; +, magnitude of effect.
Table 16-4. Comparison of the Properties of Heparin and Warfarin
PROPERTY HEPARIN WARFARIN
Route of administration
Parenteral/subcutaneous Oral
Site of action Blood (in vivo and in vitro) Liver
Onset of action Immediate Delayed; depends on half-lives of factors being
replaced
Duration of action 4 hours 2-5 days
Mechanism of action Accelerates action of antithrombin III to neutralize thrombin
Inhibits epoxide reductase, thus preventing activation of vitamin K
Laboratory control of dose
PTT PT, INR (standardizes the PT)
Antidote Protamine sulfate Vitamin K (phytonadione), fresh frozen plasma
Safety in pregnancy Yes No (fetal warfarin syndrome)
INR, international normalized ratio; PT, prothrombin time; PTT, partial thromboplastin time.
Low-molecular-weight heparins (LMWHs)
1. Examples a. Dalteparin b. Enoxaparin c. Nadroparin d. Tinzaparin 2. Mechanism of actionAntifactor Xa (mostly) and antifactor IIa activity 3. Uses
e. Anticoagulation during pregnancy
f. When needed, monitored by evaluating anti-Xa activity 4. Adverse effects
a. Bleeding b. Allergic reactions
Fondaparinux
1. Synthetic pentasaccharide anticoagulant 2. General considerations
a. Antithrombotic activity as a result of ATIII-mediated selective inhibition of factor Xa b. Elimination half-life of 18 hours; allows for once a day dosing.
3. Uses
a. Venous thromboembolism prophylaxis following orthopedic surgery b. Pulmonary embolism (PE)
c. Deep vein thrombosis (DVT)
Direct thrombin inhibitors
1. Most are derivatives of hirudin (referred to as rudins), a peptide found in leeches. 2. Examples
a. Lepirudin b. Bivalirudin c. Argatroban
3. Used for anticoagulation in patients with heparin-induced thrombocytopenia (HIT)
Oral anticoagulants (warfarin)
page 141 page 142 1. Warfarin is a synthetic derivative of coumarin, which is found in certain plants.
Coumarin derivatives are used as rat poison. 2. Mechanism of action
a. Inhibits epoxide reductase in the liver, which normally activates vitamin K that is produced by bacteria or absorbed from the diet. Warfarin inhibits epoxide reductase, which prevents activation of vitamin K.
b. Activated vitamin K γ-carboxylates the procoagulant vitamin K-dependent factors II (prothrombin), VII, IX, X and the anticoagulant vitamin K-dependent factors protein C and S (Fig. 16-4).
Procoagulant vitamin K-dependent factors include II, VII, IX, and X.
(1) All of the vitamin K-dependent factors are synthesized in the liver and are non-functional until they are γ-carboxylated. (2) Protein C and S inactivate factors V and VIII and enhance fibrinolysis.
Anticoagulant vitamin K-dependent factors also include protein C and S, which degrade factors V and VIII. c. Calcium binds to the γ-carboxylation sites on these factors, so that they can perform their functions in producing a fibrin clot or
degrading coagulation factors.
3. Genetic factors increase patient sensitivity to warfarin a. Genetic variations in the proteins CYP2C9 and VKORC1
(1) CYP2C9 deficiency is responsible for the lack of warfarin's metabolism requiring reduced dosing to prevent increased bleeding
(2) Mutations in VKORC1 require very high doses of warfarin to provide adequate anticoagulation b. A genotyping test is available to provide important guidance on initiation of anticoagulant therapy. 4. Uses (see Table 16-1)
5. Adverse effects Bleeding
If bleeding is life-threatening, fresh frozen plasma is the treatment of choice. 6. Monitoring
a. Target is a 1.5 to 3.5 fold increase in PT if human tissue thromboplastin is used (basis of the INR [international normalized ratio of test/control])
INR standardizes the PT, regardless of the reagents or instrumentation used in measuring the PT. PT is the basis for calculation of the warfarin dose.
b. Low-intensity anticoagulation (INR 1.5-2); long-term c. Moderate-intensity anticoagulation (INR 2-3); used initially
d. High-intensity anticoagulation (INR 2.5-3.5); used for mechanical prosthetic heart valves 7. Comparison of the properties of warfarin to those of heparin (see Table 16-4)
8. Contraindications a. Pregnancy
Teratogenic effects-nasal hypoplasia, agenesis corpus callosum, fetal bleeding and death Warfarin can cause fetal hemorrhage and skeletal malformations (fetal warfarin syndrome).
b. Bleeding disorders 9. Drug interactions (many)
Most relate to the cytochrome P450 system (Table 16-5).
Figure 16-4 Mechanism of action of warfarin. (From Brenner G and Stevens C: Pharmacology, 3rd ed. Philadelphia, Saunders, 2010, Figure 16-3.)