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

1. Parental A. Heparin (fractionated and unfractionated)B. Direct thrombin inhibitorsC. Drotrecogin alpha

2. Oral: A. Warfarin B. 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

Heparin

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

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 thrombocytopeniaTreatment • Discontinue all heparin• If need to continue anti-coagulation, use

danaparoid (orgaran).• Avoid platelet transfusions• Thrombosis: use danaparoid or thrombin inhibitor

(Hirudin)

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

A. 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

Synthesis of Functional

Coagulation Factors

VII

IX

X

II

Vitamin K-Dependent Clotting Factors

Warfarin

Synthesis of Non Functional

Coagulation Factors

Antagonismof

Vitamin K

Warfarin Mechanism of Action

Vitamin K

VII

IX

X

II

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.

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

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 sites4. Antibiotic eliminate the intestinal flora that produce vitamin k

this will increase the risk of bleeding

Monitoring of warfarin

• Prothrombin Time (PT)• Historically, a most reliable and “relied upon”

clinical testHowever:– 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 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

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

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

Good luck