ANTICOAGULANT BY: DR ISRAA OMAR

Definition of Anticoagulation Therapeutic interference ("blood-thinning") with the clotting mechanism of the blood to prevent or treat thrombosis and embolism.

Indications of Anticoagulant Therapy Treatment and Prevention of Deep Venous Thrombosis Pulmonary Emboli Prevention of stroke in patients with atrial fibrillation, artificial heart valves, cardiac thrombus. During procedures such as cardiac catheterisation

Enhances Antithrombin Activity

Types of anticoagulants Parental Heparin (fractionated and unfractionated) Direct thrombin inhibitors Drotrecogin alpha Oral: Warfarin Dabigatran

A. Heparin I. Standard Heparin Heterogeneous mixture of polysaccharide chains MW 3k to 30k Active in vitro and in vivo Administration - parenteral- Do not inject IM - only IV or deep S.C. Half-life 1 - 2 hrs

Heparin mechanism of action Antithrombin III Thrombin

Monitoring Heparin Activated Partial Thromboplastin Time (APTT) Normal range: 25-40 seconds Therapeutic Range: 55-70 seconds

II. Low Molecular Weight Heparin Changed management of venous thromboembolism Standard (Unfractionated) heparin 30k LMWH contains polysaccharide chains MW 5k Enriched with short chains with higher anti-Xa:IIa ratio

Differences in Mechanism of Action Any size of heparin chain can inhibit the action of factor Xa by binding to antithrombin (AT) In contrast, in order to inactivate thrombin (IIa), the heparin molecule must be long enough to bind both antithrombin and thrombin The chains of LMWH are not long enough to bind antithrombin and thrombin

Advantages of LMWH over UH No need for laboratory monitoring: when given on weight adjusted basis the LMWH anticoagulant response is reproducible and predictable. Higher bioavailability 90% vs 30% Longer plasma half life 4-6hrs vs 0.5-1 hour Renal (slower) vs hepatic clearance Less inhibition on platelet function (not shown in clinical use) Lower incidence of thrombocytopenia and thrombosis (HIT syndrome): less interaction with platelet factor 4 and fewer heparin dependent Ig G antibodies Platelet factor-4 is a protein that is released from the granules of activated platelets and binds with high affinity to heparin. In HIT, heparin binds to platelet factor 4 (PF4), the immune system forms antibodies against this complex. These antibodies are usually of the IgG class and their development usually takes about five days.

Complications of Heparin Hemorrhage (can be reversed by using protamine sulfate as an antidote) Heparin-induced thrombocytopenia (HIT) and thrombosis Osteoporosis (long-term only) more than 6 month; the explanation of this side effect is unknown Hyperkalemia Hypersensitivity reaction

Heparin-Induced Thrombocytopaenia Most significant adverse effect of heparin after haemorrhage Most common drug-induced thrombocytopenia Treatment Discontinue all heparin If need to continue anti-coagulation, use danaparoid (orgaran). Avoid platelet transfusions Thrombosis: use danaparoid or thrombin inhibitor (Hirudin) Danaparoid: inhibit activated factor X (factor Xa).it is a heparinoid but considered to be a low molecular weight heparin by some sources. However it is chemically distinct from heparin.

B. Direct thrombin inhibitors Drugs Lepirudin, desirudin, and bivalirudin, are modified forms of hirudin, the thrombin inhibitor present in the leech saliva. Mechanism of action These drugs bind to the active site of thrombin so preventing its coagulant activity.

Adverse effects Bleeding (no antidote is available) Antibody formation (50% of patient receiving lepirudin): since the drug antibody complex retains anticoagulant activity, the duration of action can be increased. Therapeutic uses As an alternative to heparin when heparin is contraindicated (patients at risk of heparin-induced thrombocytopenia, etc.).

C. Drotrecogin alpha The drug is a recombinant form of activated Protein C. Mechanism of action Inhibition of coagulation by proteolytic inactivation of factor Va and VIIIa. Adverse effects Bleeding (no antidote is available)

Therapeutic uses Given by IV infusion to patients with disseminate intravascular coagulation due to severe sepsis (the sepsis impairs the activation of protein C). In this disease the drug leads to an absolute reduction of 6% in mortality.

2. Oral anticoagulant Warfarin: Warfarin is an oral anticoagulant that prevent thrombosis. Small, lipid soluble vitamin K analogs.

Mechanism of action Vitamin K is an essential cofactor for the synthesis of coagulation factors in the liver. Vit K quinone is the active form. Oxidation of this quinone to Vit K epoxide is coupled with carboxylation of coagulation factors II, VII, IX and X, as well as the anticoagulant factors proteins C and S. Epoxide is then reconverted to quinone by Vitamin K epoxide reductase (VKOR). Warfarin blocks this reductive conversion and the carboxylation blockade results in incomplete molecules that are inactive in coagulation.

Vitamin K-Dependent Clotting Factors VII Synthesis of Functional Coagulation Factors IX X The four Vitamin K dependent clotting factors are synthesized in the liver. II

Warfarin Mechanism of Action Vitamin K Antagonism of Vitamin K VII Synthesis of Non Functional Coagulation Factors IX X Warfarin acts as an anticoagulant by blocking the ability of Vitamin K to carboxylate the Vitamin K dependent clotting factors, thereby reducing their coagulant activity. II Warfarin

Warfarin

Pharmacological effects of warfarin Warfarin action occurs only in vivo (in the liver) Warfarin has no effect on the activity on the clotting factors that are already formed. Therefore the onset of warfarin activity depends upon the rate of metabolism of these performed factors. Their half lives are: Factor II: 60 hrs Factor VII: 8 hrs Factor IX: 24 hrs Factor X: 40 hrs Protein C: 14 hrs

Therefore there is 3-5 day delay between the drug administration and the start of anticoagulant effect. Transient protein C deficiency can also be induced because protein C and factor VII have the shortest half-lives. Consequently protein C is inactivated whereas the intrinsic system remains active for a few days. This can cause transient hypercoagulability and local thrombosis.

Bleeding Hepatotoxicity Side effects: Bleeding Hepatotoxicity Warfarin induced skin necrosis (can be reduced by starting heparin and warfarin concomitantly)

Factors that may influence bleeding risk of warfarin Intensity of anticoagulation Concomitant clinical disorders (liver disease, thyrotoxicosis and fever) Quality of management Concomitant use of other medications Cimetidine and other enzyme inhibitors increase its action while rifampicin and other enzyme inducers inhibit the action of warfarin Aspirin increase its bleeding risk by working in synergistic fashion (PLATELETS INHIBITION) . NSAIDS and chloral hydrate displace it from binding sites Antibiotic eliminate the intestinal flora that produce vitamin k this will increase the risk of bleeding The major side effect of warfarin is hemorrhage. The factors that can influence the bleeding risk are shown on this slide; three of these potential risk factors, namely: the intensity of anticoagulation, concomitant use of other medications, and quality of management are controllable. The intensity of anticoagulation is an extremely important risk factor for adverse events. This is because warfarin, a narrow therapeutic index drug, has a small window of therapeutic effectiveness and dosing must be carefully managed. Such management is best achieved in the setting of an anticoagulation management service (anticoagulation clinic).

Monitoring of warfarin Prothrombin Time (PT) Historically, a most reliable and “relied upon” clinical test However: Proliferation of thromboplastin reagents with widely varying sensitivities to reduced levels of vitamin K-dependent clotting factors has occurred Problem addressed by use of INR (International Normalized Ratio) The prothrombin time (PT) is the test most commonly used to monitor warfarin dosing. The reliability of the result of the PT is influenced adversely by the variability in the sensitivity of thromboplastin reagents used by different laboratories. This problem has been markedly reduced by reporting the PT ratio as an International Normalized Ratio (INR).

Changing over from Heparin to Warfarin May begin concomitantly with heparin therapy Heparin should be continued for a minimum of four days Time to peak antithrombotic effect of warfarin is delayed 96 hours (despite INR) When INR reaches desired therapeutic range, discontinue heparin (after a minimum of four days) When short-term heparin followed by long-term warfarin are used, both anticoagulants can be started simultaneously. Heparin should be continued for a minimum of four days because the peak antithrombotic effect of warfarin is delayed for about 96 hours, independently of the INR, until Factor II (prothrombin is reduced). Heparin can be discontinued after a minimum of four days when the INR reaches the therapeutic range.

Warfarin: Dosing & Monitoring Start low Initiate 5 mg daily Educate patient Stabilize Titrate to appropriate INR Monitor INR frequently (daily then weekly) Adjust as necessary Monitor INR regularly (every 1–4 weeks) and adjust This slide provides guidelines for safe and effective warfarin use. The dose of warfarin should be monitored daily until the INR is in the therapeutic range and then less frequently when a stable dose-response relationship is achieved. Regardless of the degree of stability in warfarin dosing and INR value in the hospital, it is important to monitor the INR frequently post hospital discharge (i.e., at least 1–3 days after discharge) and to spread out the interval of monitoring thereafter depending on INR response. Monitoring is necessary in all patients, but can be reduced to four weekly intervals in the low risk (for bleeding) patient who shows a stable dose-response.

Contraindications to Warfarin Therapy Pregnancy (it is a terotogenic drug can cause maxillofacial abnormality if given in the first trimester and increase the incidence of bleeding in the new born baby in the last trimester; but it can be given in the middle trimester of pregnancy but with higher doses to achieve the target INR because there is hyper-coaguability state during pregnancy Situations where the risk of hemorrhage is greater than the potential clinical benefits of therapy Uncontrolled alcohol/drug abuse Unsupervised dementia/psychosis The relative contraindications for warfarin are listed on this slide. Warfarin crosses the placenta and is teratogenic in the first trimester, producing warfarin embryopathy in about 5% of exposed neonates. It is also fetopathic when used after the first trimester in an unknown (but much smaller) percentage of fetuses. Warfarin is contraindicated (relative or absolute) in patients with an increased risk of serious bleeding. The indication for warfarin should be reviewed carefully in patients with relative contraindications.

Warfarin Overdosage Can present with any unusual bleeding: Blood in stools or urine Excessive menstrual bleeding Bruising Excessive nose bleeds/bleeding gums Persistent oozing from superficial injuries Bleeding from tumor, ulcer, or other lesion The signs of warfarin overdosage are listed on this slide. Hemorrhagic complications from warfarin therapy are more likely to occur with excessive degrees of anticoagulation, but even with an INR in the therapeutic range, bleeding can occur. Because of the likelihood of finding an underlying lesion in an individual who has gastrointestinal bleeding or significant genito-urinary bleeding in the face of therapeutic levels of anticoagulation, one is advised to consider and evaluate for underlying abnormalities predisposing to the bleeding. The return on such evaluations in the face of an excessive degree of anticoagulation diminishes, and one must use judgement whether or not to pursue an evaluation.

Treatment of overdose Stop warfarin: in some cases only stopping the drug can be enough Plasma (fresh frozen plasma or clotting factors) Rapid but short-lasting, used mainly for life threating bleeding Vitamin K Not rapid, but lasts 1-2 weeks. Do not use if wishing to restart warfarin within next week.

B. Dabigatran Dabigatran etexilate (prodrug) Competitive inhibitor of thrombin Bioavailability: 3-7% Dabigatran etexilate is a substrate of the efflux transporter P-gp  Half-life: 12-17 hr Excretion: Urine (80%) Adverse effects: Dyspepsia and gastritis, bleeding

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