Download Pharmacology Objectives 12

Pharmacology
Lecture 12 Anticoagulant Drugs, Antiplatelet Agents, and Thrombolytic Therapy
1) Describe the antiplatelet action of aspirin. Aspirin is an irreversible inhibitor of
cyclooxygenase, which mediates the conversion of arachadonic acid to thromboxane
A2, an inducer of platelet aggregation and constriction of arterial smooth muscle.
2) List the indications for aspirin antiplatelet therapy. Aspirin is recommended in the
treatment of transient cerebral ischemic episodes (TIA), other cerebral vascular
disorders, unstable angina, and post-MI (unsure for prophylactic MI or CVA). It is
also used to maintain vein graft patency after coronary artery bypass and for patients
on long-term hemodialysis.
3) Name two antiplatelet drugs that may be used instead of aspirin.
Clopidogrel – inhibits ADP-induced platelet aggregation and release of platelet
granule constituents. It is marginally more effective and much more expensive.
Abciximab – inhibits platelet membrane glycoprotein IIb/IIIa receptors, which inhibit
the final common path of platelet aggregation. It can be used to prevent reooclusion
and restenosis following coronary angioplasty and atherectomy (high bleeding risk).
Dipyridamole w/asprin – inhibits adenosine uptake and weakly inhibits
phosphodiesterase with increase in cAMP.
4) Describe the thrombolytic action of streptokinase and tPA.
Streptokinase – a non-enzymatic protein that activates the fibrinolytic system by
forming a 1:1 stoichiometric complex with plasminogen or plasmin by binding to the
caboxy-terminal making its serine center more reactive, thereby causing the
formation of an efficient plasminogen activator.
tPA – forms an active degradative enzyme which acts on an arg-val bond of
plasminogen or plasmin when lys-plasminogen is bound to fibrin. The bound t-PA is
protected from α2 antiplasmin.
5) List the adverse reactions to the thrombolytic and antiplatelet drugs.
Thrombolytic drugs are associated with risk of bleeding (especially at injection sites),
internal hemorrhage, and death. Allergic reactions may occur with streptokinase.
Antiplatelet drugs – aspirin is associated with GI symptoms and bleeding while
clopidogrel is associated with a risk of leucopenia.
6) List the indications and contraindications for thrombolytic therapy.
Indications – given IV for myocardial infarction (within the first 6 hours) and for
acute ischemic stroke (within the first 3 hours).
Contraindications – history of peptic ulcer, insulin dependant diabetes mellitus,
internal bleeding, cerebrovascular accident, recent surgery or trauma, brain tumor,
aneurysm, bleeding diathesis, age over 70, or uncontrolled severe hypertension.
7) Name a test of control for thrombolytic therapy. Plasminogen activity can be
determined through blood tests.
Anticoagulant Drugs
1) Describe the mechanism of action of heparin and warfarin.
Heparin – binds to antithrombin III via a terminal pentasaccharide complex and
increases the rate at which it neutralizes the proteolytic activity of factor Xa and
thrombin (IIa). Unfractionated Heparin (UFH) and Low Molecular Weight Heparin
(LMWH) differ in their relative inhibitory activity. Both bind a terminal
pentasaccharide complex to antithrombin resulting in a conformational change that
increases the inhibition of factor Xa, but only the longer chains of UFH can bind both
antithrombin and prothrombin to form a prothrombin ternary complex. Therefore,
UFH has equal affect on factors Xa and IIa while LMWH has greater activity on Xa
than IIa.
Warfarin – interferes with vitamin K-dependant hepatic synthesis of prothrombin and
factors VII, IX, and X resulting in the production of these factors in biologically
inactive forms, i.e. lacking carboxyl groups needed for binding calcium. Vitamin K is
oxidized to an epoxide and then reduced back to vitamin K, but warfarin inhibits two
reductases that promote this reversion thus depleting active Vitamin K stores.
2) Contrast the distribution of heparin and warfarin.
Heparin –UFH varies in its response due to binding to plasma proteins, endothelial
cell surfaces, macrophages, and certain acute phase reactants, but LMWH has
decreased binding to nonanticoagulant proteins such that a weight adjusted dose has a
more predictable and reproducible response. LMWH has a greater bioavailability
after subcutaneous injection (90% vs 30% for UFH). IM injection is contraindicated
due to risk of hemorrhage. Heparin does not cross the placenta and is not excreted in
milk. LMWH is eliminated by the kidney and is not given in renal insufficiency.
Warfarin – is given orally because it is promptly and completely absorbed in the GI
tract. Warfarin is highly protein bound (98-99%) and the bound fraction remains
constant although individual variations exist that affect the response from person to
person. Warfarin is metabolized in the liver and eliminated in the kidney. The S
stereoisomer is 5x as potent as the R form. Both stereoisomers are metabolized
differently and are affected differently by inhibitors and inducers of cytochrome P450. Liver disease increases sensitivity but probably due more to production of
clotting factors than alterations in metabolism of warfarin.
3) Contrast the pharmacology of unfactionated heparin and low molecular weight
heparin. See question 2.
4) Describe the contraindications to the use of heparin and warfarin and the
adverse effects of each drug.
Drug
Heparin
Warfarin
Contraindications
Severe liver disease, hemophilia, active
bleeding, history of heparin-induced
thrombocytopenia
Severe liver or kidney disease, risk of
CNS hemorrhage, cerebral aneurysms,
open wounds or bleeding of the GI, GU,
or respiratory tract
Adverse effects
Hemorrhage – both UFH and LMWH
LMWH – spinal or epidural hematoma
Hemorrhage, excessive prolongation of PT
time without bleeding or minor bleeding
(dose adjustment).
Teratogenic – crosses the placenta
5) Name the test of anticoagulant control for heparin and warfarin.
Heparin therapy (UFH) is monitored with measurement of activated partial
thromboplastin time (APTT or PTT) a test that is sensitive to the effects on
thrombin, Xa, and IXa. The APTT should be at least 50 seconds correlating to a
plasma concentration of 0.2-0.4 U/mL. LMWH is rarely monitored.
Warfarin therapy is monitored with the prothrombin time assay (PT). The influence
of reagent variation on the PT is minimized through the use of the International
Normalized Ratio (INR). The INR should be between 2 and 3 for patients on warfarin
therapy.
6) List some drugs that augment or diminish the anticoagulant response to
warfarin and describe the mechanism of the interactions.
Interacting drug
Rifampin
Nafcillin
Alcohol
Metronidazole and trimethoprim
+ sulfamethoxazole
Amioderone
Aspirin and other NSAIDs
Mechanism
CYP3A4 induction
Unknown
CYP2E1 Inhibition: acute use
Induction: chronic use
Decreased metabolic clearance
of S isomer
Decreased metabolic clearance
of R and S isomers
Antiplatelet action
Effect
Loss of anticoagulant action
Loss of anticoagulant action
Increased anticoagulant effect
Decreased anticoagulant effect
Increased anticoagulant effect
Marked potentiation of
anticoagulant effects
Risk of bleeding
7) List the major clinical indications for the use of anticoagulant drugs.
Indication
Symptomatic venous thromboembolism
Deep venous thrombosis prophylaxis
Pulmonary embolism
Prevent systemic embolism
Tissue heart valves
Acute Myocardial Infarction
Valvular heart disease
Atrial fibrillation
Anticoagulant drugs
1st heparin then warfarin (3-4 day overlap) for 6-12 months
Warfarin or LMWH
1st heparin then warfarin (3-4 day overlap) for 6-12 months
Warfarin
Warfarin
1st heparin then warfarin (3-4 day overlap) for 6-12 months
Warfarin
Warfarin
8) Name the antidotes for heparin and warfarin.
Heparin – intravenous Protamine sulfate is basic and combines strongly with the
acidic heparin to form a stable complex without anticoagulant activity.
Warfarin – vitamin K is administered to replenish depleted stores and restore clotting
ability.