Say No to clots!

Anticoagulation Drugs

Ubatan yang digunakan dalam permasalahan trombosis

Beberapa permasalahan dicetuskan oleh sifat darah yang mudah berketul. Ketulan kecil yang terbentuk boleh mengancam nyawa. Pesakit mungkin datang ke jabatan kecemasan dengan serangan jantung, sesak nafas atau angin ahmar. Dalam keadaan ini, ubatan antikoagulan dapat membantu 'mencairkan' atau melancarkan semula peredran darah atau mengurangkan pembentukan ketulan..Tetapi ingat segalanya atas izin Allah....

Di bawah ini adalah kumpulan ubatab yang digunakan dalam menghalang koagulasi:
A. Drugs used in disorders of coagulation
1. Anti coagulants
2. Fibrinolytic agents
3. Antiplatelet agents


ANTI KOAGULASI

Indirect thrombin inhibitors

1. Unfractionated Heparin (UFH = HMWH)
2. Low molecular weight heparin (LMWH)
3. Fondaparinux

Heparin
• Sulfated polysaccharides. Source of commercial heparin:
– porcine intestine
– bovine lung

• Mechanism:
– Binds to and accelerates 1000x the action of ATIII (an endogenous anticoagulant). ATIII inhibit proteases: thrombin, IXa, Xa  retard thrombus formation. Heparin (co-factor) is released intact for renewed binding.

Unfractionated Heparin (UFH)

• inhibit thrombin, IXa, Xa. Route: continuos IV infusion or SC intermittent injection (rarely used except for prophylaxis), binds to heparin-binding-proteins in blood stream. Only free UFH is active. Clearance through kidney, t ½ 30-60 minutes. Heparin has pharmacokinetic limitations not shared by LMWHs  Heparin therapy is usually restricted to the hospital setting (can be monitored and its dosage adjusted frequently)

Low-molecular weight heparin (LMWH)

• inhibit thrombin (less effect on IXa and Xa. Better bioavailability, less frequent dosing requirement. Clearance: less rapidly through kidney than UFH, accumulation occurs overtime. can be administered: in-hospital or out-of-hospital setting because can be administered SC (No need for laboratory monitoring).

Fondaparinux (synthetic)

• selective inhibitor of activated factor X (factor Xa). An entirely synthetic pentasaccharide that is structurally related to the antithrombin-binding site of heparin. Compare to heparin, pentasaccharide selectively binds to antithrombin, causing it to rapidly inhibit factor Xa

Kegunaan di peringkat klinikal: Heparin clinical application
1. Langkah awal dalam merawat trombosis: Initial phase of long-term anticoagulant therapy: start with heparin or LMWH. Followed by: oral anticoagulants. (except: in pregnancy and in patients who develop recurrent venous thromboembolism while on oral anticoagulants)
2. Prevention of venous thromboembolism - venous thrombosis and pulmonary embolism (PE)
3. Early treatment of patients with unstable angina and acute myocardial infarction.
4. Patients who undergo cardiac surgery using cardiac bypass, vascular surgery, and coronary angioplasty;
5. Patients with coronary stents
6. Selected patients with disseminated intravascular coagulation.


LMWHs. Tidak begitu berbeza dari HMWH
1. Prevention of venous thromboembolism - venous thrombosis.
2. Treatment of acute PE.
3. The early treatment of patients with unstable angina

Perlu berhati hati kerana bukan semua pesakit boleh diberi heparin. Heparin contraindications
• Patient with HIT, Drug hypersensitivity, Active bleeding, Significant thrombocytopenia, Purpura, Severe hypertension, Intracranial hemorrhage, Infective endocarditis, Active tuberculosis, GIT ulcerative lesions, Threatened abortion, Visceral carcinoma, Advanced hepatic/ renal disease, Post brain, spinal cord, eye surgery. Lumbar puncture, regional anaesthesia block


Dan ingat perlu diawasi penggunaan nya: Monitoring of heparin effects
• Activated Partial Thromboplastin Time (APTT). Monitor time for a specific clotting process to occur (in the laboratory test) then compare to a “control” sample of normal blood. Unit (seconds

Kesan sampingan nya: Adverse effects
• Bleeding – careful in patient selection, control dosage, close monitoring (elderly, renal failure)
• Allergy (animal origin)
• Osteoporosis/ spontaneous fracture
• Mineralocorticoid deficiency
• Alopecia
• Heparin-induced thrombocytopenia (HIT) (systemic hypercoagulable state) – especially surgical patient on UFH bovine origin.
• Monitor platelet.

Treatment of bleeding with heparin treatment:
1. Rx: stop heparin ! Use Protamine sulfate - Use to reverse the effects of heparin (UFH). Route: Intravenous. Source: basic protein from fish sperm.1 mg will neutralise 100 IU of UFH

Direct thrombin inhibitors - bertindak secara langsung dalam penghasilan faktor koagulan

• Warfarin – dulunya racun tikus! initially used as rodenticide. 1950s – used as antithrombotic agent in human

Mechanisms of action

• Block γ-carboxylation of glutamate residues in prothrombin, factors VII, IX, X, protein C and S  formation of incomplete coagulation factor molecules  biologically inactive.
• How? - Coupled to Vitamin K oxidation
• Warfarin action is delayed: 8-12 hours delay of action (compare to Heparin – immediate effect). Why? Time taken to achieve Balanced between partially inhibited synthesis and unaltered degradation of the 4 vitamin-K-dependent clotting factors = VII, IX. X, II (t ½ = 6, 24, 40, 60 hours)

Clinical

• Administration & dosage:
– 5-10 mg loading dose. Adjust in 1/52. Maintenace dose 5-7 mg/day
– Monitor Prothrombin time (PT), therapeutic range = INR.
– Recommended INR for prophylaxis/ treatment of thrombotic disease 2-3.
– artificial heart valve/ other medical condition with thrombotic risk 2.5-3.5.
– Be aware of patient with resistant to warfarin treatment  raise target INR.

Drug interaction
• Pharmacokinetics - enzyme induction, enzyme inhibition, reduced plasma protein binding.
• Drugs that increase warfarin effect: Phenyl butazone, sulfinpyrazone
• Pharmacodynamics – synergism, competitive antagonism.
• Drugs that increase warfarin effect: aspirin, heparin

Warfarin adverse effects
• Birth defects and hemorrhagic disorder in fetus. Never administer in pregnancy
• Cutaneous necrosis
• Reduced protein C activity
•  frank infarction of breast, fatty tissues, intestine, extremities.

Reversal of warfarin action
• Stop the drug
• Administer vitamin K, fresh frozen plasma (FFP), prothrombin complex concentrates, recombinant factor VIIa
• Consider repeat administration of (2) because of warfarin long t ½


Fibrinolytic drugs - Ubatan ini menghalan penghasilan fibrin

• Mechanism:
– lyse thrombi by catalyzing the formation of serine protease PLASMIN from PLASMINOGEN. Cause generalised lytic state.

The drugs
1. Streptokinase
2. Urokinase
3. Anistreplase
4. Tissue plasminogen activators (t-Pas)
5. Reteplase
6. Tenecteplase

Clinical Indications:
• Acute myocardial infarction
• Pulmonary embolism
• Severe DVT
• Ascending thrombophlebitis

The antiplatelet- Bahan ini pula mencegah aktiviti platlet
1. Aspirin
2. Clopidogrel & ticlopidine
3. Blockade of platelet glycoprotein IIB/IIIA receptors
4. Others


Aspirin (acetylsalicylic acid)
• Prototype of NSAIDs. Mechanism: Irreversibly acetylate and inactivate cycloxygenase (COX) Inhibit synthesis of thromboxane A2,(An arachidonate product that causes platelets to change shape, release granules and aggregates). Side effects: bleeding, gastric side effects

Clopidogrel & ticlopidine
Mechanism: Block ADP receptor irreversibly. No effect on prostaglandin metabolism. Indication: TIA, completed stroke, unstable angina pectoris, patient set for coronary stent

Adverse effects
• Ticlopidine(250 mg daily):
– Leukopenia (monitor WBC count first 3 month Rx) ,
– Nausea, dyspepsia, diarrhoe,
– hemorrhage.

• Clopidogrel (75 mg daily) – fewer side effects

IIB/IIA receptor blocker
• Receptor for fibrinogen, vitronectin, vWF
• Mechanism: inhibit final common pathway for platelet aggregation
• Drugs:
1. Abciximab
2. Eptifibatide
3. Tirofiban