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

Heparin mechanism of action Heparin Antithrombin III Thrombin

Monitoring Heparin Activated Partial Thromboplastin Time (APTT) Normal range: seconds Therapeutic Range: 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

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

Other Parenteral Anticoagulants 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.).

Other Parenteral Anticoagulants 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 without undue bleeding.

LECTURE-02/Oral anticoagulant Warfarin is an oral anticoagulant that prevent thrombosis. Chemistry Small, lipid soluble vit K analogs. Warfarin is the only member of this group currently used in therapy. 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. Warfarin blocks this reductive conversion and the carboxylation blockade results in incomplete molecules that are inactive in coagulation. [Vitamin K epoxide reductase (VKOR)]

After Warfarin Administration a.Warfarin action occurs only in vivo (in the liver) b.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 1-3 day delay between the drug administration and the start of anticoagulant effect. For similar reasons the anticoagulant action can last 2-5 days after a single dose. Transient protein C deficiency can also be induced because protein C and factor VII have the shortest half-lives of the coagulation factors. Consequently protein C is inactivated whereas the intrinsic system remains active for a few days. This can cause transient hypercoagulability and local thrombosis.

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 Synthesis of Functional Coagulation Factors VII IX X II Vitamin K-Dependent Clotting Factors

Warfarin Synthesis of Non Functional Coagulation Factors Antagonism of Vitamin K Warfarin Mechanism of Action Vitamin K VII IX X II

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 1.Cimetidine and other enzyme inhibitors increase its action while rifampicin and other enzyme inducers inhibit the action of warfarin 2.aspirin increase its bleeding risk by working in synergistic fashion(PLATELETS INHIBITION). 3.NSAIDS and chloral hydrate displace it from binding sites 4.Antibiotic eliminate the intestinal flora that produce vitamin k this will increase the risk of bleeding – Quality of management

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)

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)

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

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

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

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

Thank you