1. ANTICOAGULANT
BY: DR ISRAA OMAR

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

3. 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

4. Enhances Antithrombin Activity

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

6. 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 hrs

7. Heparin mechanism of action
Antithrombin III
Thrombin

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

9. 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

10. 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

12. 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 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.

13. 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

14. 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.

15. 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.

16. 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.).

17. 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)

18. 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.

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

20. 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.

22. 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

23. 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

24. Warfarin

25. 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: hrs
Factor VII: 8 hrs
Factor IX: hrs
Factor X: hrs
Protein C: 14 hrs

26. 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.

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

28. 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).

29. 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).

30. 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.

31. 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.

32. 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.

33. 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.

34. 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.

35. 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: hr
Excretion: Urine (80%)
Adverse effects: Dyspepsia and gastritis, bleeding

36. Good luck