Anti- Coagulant drugs Flashcards
Learning outcomes
- Describe the clinical pharmacology of unfractionated and low molecular weight heparins and other parenteral anti-coagulants including hirudins and fondaparinux sodium
- Recognise the use of protamine sulfate to treat heparin overdose
- Describe the clinical pharmacology of oral anticoagulants including warfarin and newer agents such as dabigitran and rivaroxaban
- Recognise the importance of monitoring the international normalised ratio (INR) for patients on warfarin therapy and describe how to manage warfarin-induced haemorrhage
- Discuss the endogenous and exogenous influences on warfarin’s effect and why this is important for a drug with a ‘narrow therapeutic window’
- Contrast the advantages and disadvantages of newly developed oral anticoagulant drugs over established anticoagulants
Arterial and venous thrombosis
Arterial circulation- More quick flow under higher pressure- less time for thrombus formation: atherosclerosis and other wall defects more likely to cause thrombosis
Venous circulation- can be stasis of flow, more extensive fibrin network may form and a thrombus can occur in VC
Drug targets in thrombosis
•Platelet function (antiplatelet drugs)
•Enhance fibrin breakdown
(fibrinolytic drugs –alteplase, streptokinase as an alternative to mechanical reperfusion via PCI)
•Blood coagulation (fibrin formation)(ANTICOAGULANT DRUGS)
Anti- Coagulant drugs
•Heparin
–unfractionated (UFH) (requires aPPT monitoring time)
–low molecular weight (LWMH)
•Coumarins (Warfarin)
•Non-Vitamin K (direct) oral anticoagulants (NOACS/DOACS) (N-non vit k/ D- directing acting)
*Anticoagulants are of greater use in preventing thrombus formation in veins than arteries, for in faster-flowing vessels such as arteries thrombi are composed mainly of platelets with little fibrin
Heparin- properties and mechanism of action
- First extracted from dog liver in 1916 –Greek –HEPARin
- Released from intact blood vessel endothelium to prevent uncontrolled clotting
- Family of glycosaminoglycans of variable chain length (3-30 kDa), unfractionated heparin(UFH)
- Fractionated into low-molecular weight heparin (LMWH) 3-7 kDa, longer duration and more predictable anticoagulant effect e.g. enoxaparin sodium
•binds to and activates anti-thrombin III (ATIII)
•UFH-ATIII complex then inactivates thrombin (IIa) and Xa
•LMWH not long enough to inactivate thrombin (IIa) so main effect is to inactivate Xa
Unfractionated heparin forms scaffold for antithrombin 3 to bind and be activated- it inhibits factor 10 and 2 (thrombin)
Less thrombin activity, less conversion of fibrinogen to fibrin
LMWH binds ATIII: but due to shorter length it only enchances f10 activity, will still lead to reduction of fibrinogen to fibrin conversion
Heparin- pharmacokinetics
- large, highly charged molecules so cannot be absorbed by the GIT
- UFH given intravenously (and subcutaneously)–immediately active, T½ 40-90 minutes (> at higher dose as metabolic pathways in liver saturate)
- LMWH given subcutaneously–longer T½ , once or twice daily dosing–renal excretion, caution/dose adjustment in renal failure
Heparin/ LWMH- Uses and adverse effects
•Treatment of
–thromboembolic disease (DVT /PE) initially together with warfarin (and instead of warfarin in pregnancy)
–(acute coronary syndrome)
–(acute peripheral arterial occlusion): last 2 less useful in arterial circulation
- Prevention of thromboembolicdisease (DVT/PE) –esp. before surgery in high risk patients
- Extracorporeal circuits (haemodialysis)
Adverse effects
•haemorrhage (bleeding gums)
–avoid in bleeding disorders, gastric ulcer
–reversed with protamine sulphate (chemical antagonism)
•reduced aldosterone secretion / hyperkalaemia
•rarely osteoporosis and alopecia (>6months treatment)
•hypersensitivity reactions (to animal heparins)
Thrombocytopenia (reduced platelet count)
–transient early, relatively common (~25% patients)–rarely severe, potentially fatal, immune-mediated HIT, >50% drop in platelet count seen 5-10 days after treatment onset (~1% patients), accompanied by rash, thrombosis–routinely monitor platelet count, measure heparin-platelet antibodies, switch to another anticoagulant if required (consult haematologist)
Heparin- monitoring
•UFH given as iv bolus then infusion adjusted by activated partial thromboplastin time (APTT)
–APTT uses a thromboplastin with no Tissue Factor activity
–tests intrinsic and final common pathways (contrast with INR which tests extrinsicand final common pathways)
–aim for 1.5-2.5 x control
•LMWH (low molecular weight) Does NOT affect APTT–if need to assess effect can measure Factor Xa activity (but rarely done)
Coumarins- warfarin
- spoiled, sweet clover (fungal-infected silage) 1920s
- Wisconsin Alumni ResearchFoundation, -ARIN(coumarin)
- marketed as rat poison 1940s
- approved for medical use as oral anticoagulant in 1954
Warfarin- mechanism of action
- inhibitor of Vitamin K epoxide reductase, preventing regeneration of reduced Vitamin K needed for clotting factor synthesis
- blocks synthesis of Vitamin K-dependent clotting factors (prevents post-translational gamma-carboxylation of II, VII, IX, X)
- onset of anti-coagulant effect delayed for a few days until already formed active factors degraded–LMWH used as initial therapy to cover this delay
- duration of action 2-5 days
VII of extrinsic, IXa in intrinsic, and Xa and Thrombin (IIa) of final pathway affected by warfarin- thrombin will not cause fibrinogen > fibrin
Warfarin- uses
- Prophylaxis (prevention) and treatment of thrombo-embolic disease (DVT / PE)
- Prophylaxis in atrial fibrillation (to reduce risk of stroke)
- Prophylaxis with prosthetic heart valves fitted (prevent valve emboli)
Dose and monitoring of warfarin
- Check baseline prothrombintime (PT)
- Loading dose for 1-3 days
- Determine the International Normalised Ratio(ratio of patient’s PT and control sample)
- Adjust maintenance dose based on serial INR
- Aim for INR value for the given condition–e.g. DVT, PE, AF: 2.5; mechanical valves: 3.5
- INR is monitored at warfarin clinic throughout treatment period
Consider risk:
of bleeding (HASBLED)
of stroke in AF (CHA2 DS2VASc)
Warfarin- adverse effects and contraindications
- Haemorrhage / High INR–including gingival bleeding
- Unexplained fall in Hb
- Gastrointestinal upset–including mouth ulcers, taste disturbance
- Teratogen (avoid in pregnancy) (can cross placenta and cause malformation of foetus)
- Alopecia
- Skin /soft tissue necrosis
Contraindications •Pregnancy •Active bleeding •Peptic ulcer (recent) •Uncontrolled severe hypertension •Bacterial endocarditis Relative contraindications •Recent surgery •Liver / renal impairment
Haemorrhage on warfarin
•If major bleeding can consider:
–Vitamin K (oral or slow iv)
–Prothrombin complex concentrate or Fresh Frozen Plasma (FFP)
•If INR <8 and NO bleeding –withdrawal of warfarin often all that’s needed
•If INR >8 with no/only minor bleeding, stop warfarin but base need to reverse on the individual’s risks
Variation in warfarin effect
- Diet
- Diseases–acute /chronic liver disease–congestive heart failure–small bowel disease
- Genetic variation–Vitamin K epoxide reductase–Cytochrome P450-2C9: warfarin metabolism in the liver
- Drug interactions
