Anticoagulants

Prepared by

Ph. Sara Saber

Sep 2015

Outline

Normal hemostasis Pathophysiology Risk factors of antithrombotic

therapy Parenteral and oral anticoagulants Patient care and monitoring. Role of clinical pharmacists in

management of patients on anticoagulants

Hemostasis

The normal physiological response that prevents significant blood loss following vascular injury.

It is a finely tuned process that serves to maintain the integrity of the circulatory system. However, the process can go out of balance, leading to significant morbidity and mortality

Major constituents of hemostatic pathways

I- Endothelium

II-Platelets

III- Coagulation Cascade

The coagulation process that leads to haemostasis involves a complex set of protease reactions involving roughly 30 different proteins.

• The final result of these reactions is to convert fibrinogen, a soluble protein, to insoluble strands of fibrin. Together with platelets, the fibrin strands form a stable blood clot.

Cont

Coagulation Factors

Factor NameI FibrinogenII ProthrombinIII Tissue Factor or

thromboplastinIV Ca++V ProaccelerinVII ProconvertinVIII Antihemophilic A

factorIX Antihemophilic B

factor or Christmas factor

Factor NameX Stuart or Stuart-Prower factorXI Plasma thomboplastin

antecedentXII Hageman factor, contact factorXIII Fibrin stabilizing factor

Prekallikrein factorHigh-molecular-weight kininogen

What happens when blood vessel is injured?

Abnormal Hemostasis

Major disease states associated with thrombosis

Venous thromboembolism (VTE).PE.CAD( Angina ,MI).Cardioembolic stroke.

Virchow’s Triad

Antithrombotic Agents MOA

Classification

A-Unfractionated Heparin C

A heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans

Heparin is usually stored within the secretory granules of mast cells and released only into the vasculature at sites of tissue injury.

MOA It acts at multiple sites in the normal coagulation system. Heparin interacts with antithrombin (heparin cofactor) to change its

conformation and enhance its ability to inhibit thrombosis by inactivating clotting factor proteases, especially thrombin (IIa), IXa and Xa by forming equimolar complexes with them.

MOA

Dosing

Numerous concentrations available; extreme caution is required to avoid medication error

Monitoring

The most widely used test is aPTT with therapeutic range defined as 1.5-2.5 times the control aPTT value.

Over dose

1 mg protamine sulphateper 100 units of UFH, up to a maximum of 50 mg, given as slow IV infusion over 10 minutes.

II-Low molecular weight heparins (LMWHs) B

Produced by either chemical or enzymatic depolymerization .

LMWHs are fragments of UFH approximately one third the molecular weight of UFH.

Although all the LMWHs share similarities in their mechanisms of action with UFH, their molecular weight distributions vary, resulting in differences in their activity against factor Xa and thrombin, affinity for plasma proteins, propensity to release tissue factor pathway inhibitor, and duration of activity.

MOA

Dosing Dosing recommendations may differ according to indication

1.5 mg/kg SC once daily or 1 mg/kg SC twice daily; if CrCl is less than 30 ml/min: 1 mg/kg SC once daily

175 units/kg SC once daily

200 units/kg SC once daily or 100 units /kg SC twice daily

Prophylaxis

Prophylactic dose of Enoxaparin is•4omg OD - 30mg BID.•If crcl less than 30ml/min 30mg OD.

Routine monitoring of anticoagulation activity and dose adjustments are not required in majority of patients

Monitoring

How does HIT occur?

Heparin injection immune reaction with body produce antibody against heparin& also bind to platelet receptor activation of platelet thrombosis .

III-Factor Xa Inhibitors B

Advantages of Factor Xa InhibitorsIt is a synthetic drug so cannot transmit animal pathogens.•Consistent from batch to batch•Rapid onset of activity.•Long half-life , predictable response.•Do not require routine coagulation monitoring or dose adjustments.•They do not affect platelet function and do not react with heparin platelet factor-4 (PF-4) antibodies seen in patients with HIT.

Fondaparinux - Rivaroxiban - Apixaban.

Fondaparinux

Fondaparinux is FDA approved for treatment of DVT and PE.Exerts inhibitory activity against factor Xa and has no effect on thrombin.

Dosing

IV-Direct Thrombin Inhibitors

They bind thrombin and prevent interactions with its substrates.

They differ in terms of their chemical structure, molecular weight, and binding to the thrombin molecule.

No platelet interaction that can lead to HIT They are the drugs of choice for treatment of VTE

in patients with a diagnosis or history of HIT

MOA

Antidote

Currently no antidote In the event of major bleed- Fresh frozen plasma- Factor concentrates- rFactor VIIa

Oral Anticoagulants

Warfarin.

Rivaroxaban and apixaban. Dabigatran.

I-Warfarin X

Warfarin is the anticoagulant of choice when long-term or extended anticoagulation is required.

Warfarin has a narrow therapeutic index Many drug interactions Many dietary interactions Requires frequent dose adjustments, significant

patient and family education and careful patient monitoring.

MOA

Synthesis of non functional coagulation factors

Antagonism of Vitamin K

Vitamin K

Warfarin

6-8 hrs

20-30hrs

24-40 hrs

60-100 hrs

VIIIX

X

II

N.B Warfarin also inhibits the production of the anticoagulant proteins C and S

PK

Warfarin is commercially available as a racemic mixture of R and S isomers.

The S isomer is two to five times more potent than the R isomer.

Metabolism of warfarin is isomer-specific. The CYP 2C9 enzyme metabolizes the S isomer, whereas the

CYP 1A2 and CYP 3A4 enzymes metabolize the R isomer

Monitoring Warfarin Therapy (PT)

International Normalized Ratio: INR

A mathmatical correction (of the PT ratio) for differences in the sensitivity of thromboplastin reagents.

In normal individuals INR=1. Target INR is usually 2-3 except in patients with

mechanical prosthetic valves it is 2.5-3.5 .

Factors that may influence bleeding risk

Concomitant drugs Concomitant diseases Quality of management Age

Conversion from Heparin to Warfarin

May begin concomitantly with heparin therapy Heparin should be continued for a minimum of five

days When INR reaches desired therapeutic range,

discontinue heparin

Warfarin Overdose Antidote

Follow the algorithm for the management of an elevated INR in patients taking warfarin

Low-dose vitamin K 2.5 mg orally or 0.5 to 1 mg via slow IV or SC injection.

Fresh whole blood, fresh frozen plasma, or plasma concentrates of vitamin K–dependent clotting factors may be helpful in reversing warfarin effects.

Drug Interactions

Dietary Interactions

Patient Education

•Introduction to the patient about the drug and the disease.•How to take warfarin?•Laboratory tests•Things that affect warfarin therapy•Problems with warfarin therapy•Preventing clots and bleeding

II-New oral anticoagulants

Advantages of New Anticoagulants over WarfarinRapid onset of anticoagulant effect, more predicatable pharmacokinetics, lower potential for clinically important interactions with food, lifestyle and other drugs.There is no requirement for routine monitoring and dose adjustments as required with warfarin.

The three drugs, dabigatran, rivaroxaban and apixaban resulted in lower rates of hemorrhagic stroke and intracranial hemorrhage in phase III clinical trials compared to warfarin. But concerning gastrointestinal bleeding, only apixaban showed no increase in gastrointestinal bleeding compared with warfarin.

Disadvantages of New Anticoagulants

Absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation.

No means to monitor drug-drug interactions

Warfarin is Fighting to Stay Alive

• Excellent efficacy• Low cost• Long track record (1954)• Point-of-care testing

Rivaroxaban: C

• Prevention of stroke and systemic embolism in adult patients with one or more risk factors, such as congestive, heart failure , hypertension, age ≥ 75 years, diabetes mellitus.

• DVT prophylaxis after knee replacement therapy, DVT prophylaxis after hip replacement therapy, prevention of thromboembolism in atrial fibrillation, and to treat and reduce the risk of DVT or PE.

• Does not require monitoring for dosage adjustments in contrast to warfarin

Apixaban: B

To reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation

Black Box Warnings: Increased RISK of STROKE & SPINAL/EPIDURAL HEMATOMA StrokeDiscontinuing rivaroxaban to patients with non-valvular atrial fibrillation increases the RISK of stroke. If rivaroxiban must be discontinued for a reason other than pathological bleeding, administration of another anticoagulant should be considered.

SPINAL/EPIDURAL HEMATOMAEpidural or spinal hematomas have occurred in patients taking rivaroxiban who are receiving neuraxial anesthesia, or undergoing spinal puncture. Such hematomas may result in long-term or permanent paralysis.

Dabigatran etexilate C

Dabigatran etexilate is a new oral direct thrombin inhibitor and the prodrug of dabigatran.

Reducing the risk of stroke and serious blood clots in certain patients with atrial fibrillation.

Dabigatran is a direct thrombin inhibitor. It works by preventing the formation of a blood clot.

Dose

The recommended dose of Pradaxa is 220 mg once daily taken as 2 capsules of 110 mg.Patients with moderate renal impairment (creatinine clearance (CrCL) 30-50 mL/min) reducing the dose to 75mg twice daily.It is not recommended in pt with sever renal impairment (crcl <30ml\min).

At initiation of therapy

Closely monitor patients receiving anticoagulant therapy for signs and symptoms of bleeding, including epistaxis, hemoptysis, hematuria, bright red blood per rectum, severe headache, and joint pain.

If major bleeding occurs, stop therapy immediately and treat the source of bleeding.

Closely monitor patients for potential drug-drug and drug-food

interactions and adherence with the prescribed regimen. Measure PT/INR at least weekly during initiation of warfarin therapy

and monthly when anticoagulation is stable

References

Chisholm-Buans MA, Wells BG, Schwinghamver TL, et al. Pharmacotherapy Principles and Practices, 3rd ed, 2013.

•Norgard NB, DiNicolantonio JJ, , Topping TJ, Wee B. Novel anticoagulants in atrial fibrillation stroke prevention. Ther Adv Chronic Dis. 2012; 3(3): 123 –136

•ELIQUIS FDA prescribing information available at www.Drugs.com, last accessed June 2013

•Pradaxa FDA prescribing information available at www.Drugs.com, last accessed June 2013

Xareleto FDA prescribing information available at www.Drugs.com, last accessed June 2013.

•http://healthcare.utah.edu/thrombosis, last accessed June 2013