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. 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

6. Heparin mechanism of action
Antithrombin III
Thrombin

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

8. 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

9. 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

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

15. 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)

16. 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

17. 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

18. 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

19. Warfarin

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

21. 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).

22. 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).

23. 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.

24. 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.

25. 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.

26. 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.

27. 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

28. Thank you