*3.1.4. Interactions*

**3. Parenteral anticoagulants**

92 Anticoagulant Drugs

of about 5000 Da [45].

*3.1.2. Indications*

*3.1.3. Pharmacokinetics*

*3.1.1. Mechanism of action*

**3.1. Heparins and low-molecular-weight heparins**

IX and neutralizes factor Xa by activating factor X inhibitor.

Heparan sulfate (HS) proteoglycans play vital functions in many biological processes in the animal kingdom, and the GAG moiety is essential for these functions. Heparin is synthesized from UDP-sugar precursors as a polymer of alternating D-glucuronic acid and N-acetyl-Dglucosamine residues [44]. Unfractionated heparin (UFH) is a glycosaminoglycan consisting of heterogeneous mixture of polysaccharide chains with alternating residues of D-glucosamin and uronic acid, glucoronic acid, or iduronic acid, with a molecular weight range of 3000– 30,000 Da. Low-molecular-weight heparins (LWMHs) are fragments of UFH produced by controlled enzymatic or chemical depolymerization processes with a mean molecular weight

Both UFH and LMWHs exert their anticoagulant activity by inhibiting thrombin-activated conversion of fibrinogen to fibrin [46]: binding of a unique pentasaccharide to antithrombin causes a conformational change in antithrombin that accelerates its interaction with thrombin and factor Xa by about 1000 times. Binding of the pentasaccharide to antithrombin results directly in inhibition of factor Xa, and the pentasaccharide also blocks the activation of factor

Heparins, and in particular LMWHs, indications comprehend: DVT prophylaxis during perioperative or postoperative period of general/orthopedic surgery or in bedridden patients; DVT treatment in patients affected by pulmonary embolism; instable angina and non-ST-elevation myocardial infarction (NSTEMI) prophylaxis with concomitant use of acetylsalicylic acid; coagulation prevention in patients undergoing dialysis; and symptomatic VTE (proximal DVT and/ or pulmonary embolism) to reduce the recurrence of VTE in patients with solid tumor cancers.

Heparin is not absorbed orally and therefore is administered parenterally. The two preferred routes of administration are continuous intravenous infusion or subcutaneous injection. If administered subcutaneously, the dose of heparin should be higher than the usual intravenous dose because subcutaneous administration is associated with reduced bioavailability [46]. UFH does not have predictable pharmacokinetics, and it has a small volume of distribution and a relatively short half-life of about 0.5–1 hour [47]. After injection heparin rapidly disappears from blood: the rapid, saturable elimination phase is thought to reflect UFH binding to vascular endothelial cells, macrophages, and reticuloendothelial cells, where it is internalized and metabolized into smaller and less sulfated forms [48]. At higher doses, the cellular binding sites are saturated, and heparin is cleared predominantly by renal elimination [49]. UFH binds also to plasma proteins, changing its pharmacokinetic profile and reducing its Heparin use should be avoided in case of concomitant treatment with antiplatelet drugs (NSAIDs, diclofenac, piroxicam, ketorolac, nimesulide, and acetylsalicylic acid), anticoagulant agents (warfarin), and glucocorticoids, due to increase in bleeding risk. Furthermore, LMWH should not be used in patients with previous heparin-induced thrombocytopenia/ thrombosis (HITT), known hypersensitivity or adverse reaction to LMWH (dalteparin or enoxaparin), severe renal impairment, active bleeding, severe or uncontrolled hypertension, active peptic ulcerations, hemophilia, and severe liver disease.

## *3.1.5. Therapy management*

Heparin therapy for VTE treatment is typically administered by continuous intravenous infusion, but adjusted dose and fixed dose subcutaneous injections can also be utilized. Obese patients clear LMWHs faster than nonobese patients due to hyperfiltration, and their dose should be adjusted on total body weight or LMWHs should be substituted with UFHs [51]. Therapy monitoring comprehends regular CrCl, platelet count, and antifactor Xa assay measurements.

In case of VTE prophylaxis, dosing and duration of LMWHs follow this pattern:


Dosing recommendations for treatment of NSTEMI with enoxaparin take into account renal functions and concomitant therapies with antiplatelet agents. In particular:


In case of thrombolysis, anticoagulation is generally given in addition to dual antiplatelet therapy at doses adjusted on patient's age:

• age < 75 years, 30 mg i.v. bolus immediately prior to thrombolysis followed within 15 minutes by 1 mg/kg subcutaneously every 12 hours (each dose should not exceed 100 mg);

Idraparinux has a longer elimination half-time of 120 h after a single administration and accumulation does occur and after more than 6 months of treatment, the elimination half-time is increased up to 60 days. It is administered once weekly and is thereby suitable for long-term anticoagulation [57]. Idrabiotaparinux was evaluated for treatment of VTE and for stroke pre-

Real-World Safety of Anticoagulants http://dx.doi.org/10.5772/intechopen.78023 95

Hirudin is a direct thrombin inhibitor (DTI) derived from the salivary secretions of leech (*Hirudo medicinalis*). Lepirudin and desirudin are two forms of recombinant hirudin, structurally identical except for minute differences in the amino-terminus sequence [59]. Unlike heparin and others anticoagulants, DTIs do not need antithrombin to perform its anticoagulant action: epirudin and desirudin form a bivalent irreversible complex with thrombin, while

Lepirudin and desirudin have been evaluated for the prevention and treatment of VTE and in patients with acute coronary syndrome (ACS). These drugs are generally more effective than heparin in prevention of thrombosis but lead to more bleeding complications possibly related to their irreversible binding to thrombin [60]. Their indications of use comprehend: treatment and prevention of suspected or proven HIT; VTE prophylaxis after hip or knee arthroplasty. Lepirudin and desirudin are administered intravenously or subcutaneously and have a half-life of 80 and 60–120 minutes, respectively. The excretion is totally renal. Due to their narrow therapeutic range, therapy monitoring should be done regularly through aPTT,

Bivalirudin is used in treatment of patients with unstable angina undergoing PCI even if at risk of HIT. This is a synthetic analog of hirudin that forms a reversible, high-affinity complex with thrombin [61]. Consequently, bivalirudin has a shorter half-life (25 minutes) and is a weaker thrombin inhibitor compared to hirudin, with a potentially larger therapeutic window. Its clearance is for 80% enzymatic and for 20% renal. Bivalirudin is now one of the preferred drugs for patients undergoing PCI in American and European guidelines, and it has

Argatroban is a small, univalent competitive inhibitor of thrombin. It binds selectively and reversibly to the active site of thrombin and has a short elimination half-life of 50 min through hepatobiliary clearance. Since it is metabolized in the liver, it should be used with caution in patients with liver failure. Argatroban has been approved for the prevention and treatment of VTE in patients with HIT [46, 47] and for patients with (a history of) HIT who need to undergo PCI [46, 63].

Department of Neurosciences, Psychology, Drug Research and Child Health, Section of

become one of the most widely used antithrombotics in the USA for PCI [62].

vention in patients with AF, resulting as safe and efficient as idraparinux [58].

**3.3. Irudin, lepirudin, desirudin, bivalirudin, and argatroban**

activated clotting time (ACT), and anti-Xa assay evaluation.

Niccolò Lombardi, Giada Crescioli and Alfredo Vannacci\* \*Address all correspondence to: alfredo.vannacci@unifi.it

Pharmacology and Toxicology, University of Florence, Florence, Italy

**Author details**

hirudin binds to both the active site as well as to exosite I on thrombin.


Intravenous anticoagulation with UFHs in addition to antiplatelet therapy is recommended for all patients undergoing primary percutaneous coronary intervention (PCI). Anticoagulant therapy is selected according to patient's ischemic and bleeding risks (70–100 units/kg i.v. bolus or 50–70 units/kg i.v. bolus with GPIIb/IIIa inhibitor). Bivalirudin or intravenous enoxaparin (0.5 mg/kg i.v.) may be used as alternatives to UFH.
