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

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 - monitor APTT Adverse effect - haemorrhage – antidote - protamine sulphate

Heparin mechanism of action Antithrombin III Thrombin

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

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

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

Trreatment of HIT Discontinue all heparin If need to continue anti-coagulation, use danaparoid (orgaran). Avoid platelet transfusions Thrombosis: use danaparoid or thrombin inhibitor(Hirudin)

Oral anticoagulant Warfarin is an oral anticoagulant that prevent thrombosis It inhibit the enzymatic reduction of vitamin K to its hydroquinone form, interfering with the post transtional modification (carboxylation) of glutamic acid residues in clotting factors 2, 9, 7, 10. Warfarin acts only in vivo

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

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

Warfarin: Major Adverse Effect—Haemorrhage Factors that may influence bleeding risk: Intensity of anticoagulation Concomitant clinical disorders(liver disease ,thyrotoxicosis and fever ) 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 Quality of management 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).

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 erotogenic 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.

Signs of Warfarin Overdosage 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.

Reversing action of warfarin 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. In some cases only stopping the drug can be enough

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