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81 PHARMACOLOGY OF BLOOD AND BLOOD VESSELS
c. Inactivation is due to metabolism, which follows zero–order kinetics.
Increasing the dose increases the time to eliminate 50% of the drug.
3. Heparin has two major effects and several minor effects.
a. One major effect is the formation of an inactive thrombin complex by cat-alyzing the reaction between antithrombin and thrombin (factor IIa).
b. The other major effect is complexing and inactivation of factor Xa.
c. Minor effects of heparin include the complexing of factors XIIa, XIa, and IXa of the intrinsic pathway.
d. The onset of action is immediate.
e. The goal of treatment is to increase the activated partial thromboplastin time (aPTT) by approximately 2 times the normal value. The aPTT should be meas-ured after 4–5 half lives (approximately 6 hours).
4. Side effects include:
a. Hemorrhage
b. Heparin-induced thrombocytopenia (HIT), which can be immunologically or nonimmunologically mediated
i. Type I HIT occurs early after initiation of therapy and involves a mild decrease in platelet count that is not immunologically mediated.
XII XIIa
XI XIa
IX IXa
Xa
VIIa VII
Prothrombin (II) Thrombin (IIa)
Fibrinogen Fibrin
X X
Synthesis of these factors is inhibited by coumarins These factors are
inactivated by heparin-antithrombin complex
Extrinsic pathway Intrinsic pathway
++ + + +
+
Figure 6-1 Intrinsic, extrinsic, and common pathways of the coagulation cascade. From Howland RD. Lippincott’s Illustrated Reviews: Pharmacology. 3rded. Baltimore: Lippincott Williams & Wilkins, 2005: 233, fig. 20.10.
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82 CHAPTER 6
ii. Type II HIT typically occurs within 5–14 days after initiation of treatment, although it can occur earlier in a previously sensitized patient.
(a) The platelets are activated by IgG antibodies against heparin, caus-ing thrombosis and a severe thrombocytopenia.
(b) Type II HIT can be fatal if not recognized. Heparin treatment should be discontinued immediately.
c. Allergic reactions or anaphylaxis
d. Osteoporosis and mineralocorticoid deficiency after long-term use
5. A mild heparin overdose can be treated by discontinuing administration of heparin.
Protamine, a basic compound that complexes heparin, is the antidote for heparin and can be administered to treat a more serious heparin overdose.
D. LOW-MOLECULAR-WEIGHT HEPARINS (LMWHs), e.g., enoxaparin (Lovenox), dalteparin (Fragmin)
1. Act preferentially on factor Xa but still have some effect on factor IIa. Monitor Xa concentration rather than aPTT.
2. Are better absorbed after subcutaneous injection than heparin.
3. Are eliminated by the kidney, by first-order kinetics. They should not be used in patients with renal failure.
4. Have a more predictable dose-response relationship than heparin.
5. Have a lower incidence of thrombocytopenia than heparin.
6. Have a longer half-life than heparin (4 hours versus 2 hours, respectively).
E. FONDAPARINUX (Arixtra) is the active pentasaccharide portion of heparin.
1. It exclusively inactivates factor Xa and cannot inactivate factor IIa.
2. The benefits of fondaparinux are that it has a long half-life (15 hours) and does not appear to cause heparin-induced thrombocytopenia (HIT).
3. Care must be taken when administering fondaparinux as its activity is not reversible with protamine.
F. DANAPAROID (Orgaran) is another inhibitor of factor Xa that has similar properties to the LMWHs.
1. It is a mixture of heparan sulfates, dermatan, and chondroitin.
2. Because danaparoid does not contain any heparin or heparin fragments, it can be used to treat patients who have developed HIT type II due to heparin treatment.
G. DIRECT THROMBIN INHIBITORS prevent coagulation by inhibiting thrombin.
1. Lepirudin (Refludan) is a peptide that irreversibly inactivates thrombin.
a. It can be used in patients who have developed type II HIT.
b. The most serious side effect of lepirudin is bleeding. The aPPT should be mon-itored as for heparin therapy.
c. Patients treated with lepirudin may develop drug–antibody complexes. These complexes are pharmacologically active and are eliminated more slowly than the drug alone.
d. Lepirudin is eliminated by the kidney and should be used with caution in patients who have renal failure.
2. Bivalirudin (Angiomax) can also be used to treat patients who have type II HIT. It has a shorter half-life than lepirudin.
3. Argatroban (Novastan) also has a short half-life. Unlike lepirudin and bivalirudin, which bind to both the active site and the substrate-recognition sites on thrombin, argatroban binds only to the active site of thrombin.
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H. WARFARIN (Coumadin, Panwarfin) is an oral anticoagulant.
1. Blockade of the reduction of vitamin K to its active form decreases the carboxy-lation and synthesis of vitamin K-dependent clotting factors (II, VII, IX, and X) as well as protein C and protein S. (See Figure 6-2.)
a. The onset of action is delayed (8–12 hours), because stores of the clotting fac-tors must be depleted.
b. The maximum anticoagulant effect of warfarin occurs after 1 week of adminis-tration.
c. The therapeutic goal is an International Normalized Ratio (INR) of 2 to 3, which will approximately double the prothrombin time.
2. Because warfarin is effective when given orally, it is more useful than heparin for outpatients.
3. Many drug interactions can occur.
a. Extensive plasma protein binding (99%) can result in competition with other drugs for the binding sites.
b. Metabolism of warfarin in the liver can be enhanced or inhibited by many other drugs.
i. Azole antifungals and cimetidine increase the concentration of warfarin due to inhibiting CYP 450 enzymes.
ii. Rifampin and barbiturates decrease the concentration of warfarin by inducing CYP 450 enzymes.
4. Side effects include:
a. Hemorrhage, which can be reversed by the antidotes vitamin K or vitamin-K dependent clotting factors.
C O
CH NH CH2 CH2 COO−
Polypeptide precursors of clotting Factors II, VII, IX, and X
NADPH NADP+ Vitamin K
reduced
Vitamin K epoxide
C O
CH NH O2
CO2
glutamyl (Gla) residue γ
Active clotting Factors II, VII, IX, and X CH2
CH O
C O− C OO
-Warfarin
Figure 6-2 Inhibition of vitamin K epoxide reduction by warfarin. From Howland RD. Lippincott’s Illustrated Reviews:
Pharmacology. 3rd Ed. Baltimore: Lippincott Williams & Wilkins, 2005: 237, Fig. 20.19.
83 PHARMACOLOGY OF BLOOD AND BLOOD VESSELS
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i. Mild hemorrhage can be reversed by stopping administration of warfarin.
ii. Severe hemorrhage may require a blood or plasma transfusion.
b. Skin necrosis, due to thrombosis of the microvasculature in the skin.
c. Teratogenicity, because it readily crosses the placenta and affects bone forma-tion in the developing fetus.
5. Acute anticoagulant therapy is often initiated with both heparin and warfarin.
a. Initially, warfarin inactivates Protein C and Protein S and has a procoagu-lant effect.
b. Thus, it is necessary to overlap warfarin administration with heparin in states of high thrombotic risk.
c. As the warfarin becomes effective, the heparin is withdrawn.
6. Warfarin and heparin slow the production of a clot, but they do not dissolve clots.