Anticoagulant Drugs (Dawes) Flashcards
Are the the indications for anticoagulants? (when do we use anti-coagulants?)
1) Arterial disease (anti-platelets + anticoagulants) include:
-
Coronary artery disease
- Acute coronary syndrome (STEMI, NSTEMI, acute chest pain etc.)
- Blood supplying the heart
- Acute coronary syndrome (STEMI, NSTEMI, acute chest pain etc.)
-
Cerebrovascular disease
- (e.g. stroke)
- Peripheral vascular disease
2) Thrombo-embolic disease (anticoagulants) include:
-
Atrial fibrillation
- (arrhythmia that’s associated with high risk of developing systemic emboli)
-
Venous thromboembolism
- (DVT, PE) (acutely give someone an anticoagulant and also over the next few months)
-
Prosthetic cardiac valves
- (Metal heart valves are very thrombogenic, activates the coagulation cascade causing thrombi to form on the unnatural metal heart valves, requires a lifetime of concurrent anticoagulant)
Describe the Virchow’s Triad and its indications for anticoagulant use
Describe the uses of Unfractionated Heparin
Its uses include:
- Acute coronary syndromes
-
Thromboembolism (prophylaxis and treatment)
- Venous: DVT, PE (although LMWH used much more commonly)
- Arterial: AF
-
Temporary “warfarin replacement”,
- e.g. pregnancy (you can’t use warfarin as anticoagulant during pregnancy)
Describe The Molecular design of UH
Unfractionated heparin consists of _linear mucopolysaccharide chains (_highly negatively charged, very heterogeneous, vary greatly in molecular weight 3,000-40,000).
It is mix of v_ariable length heparin chains_ (pig intestinal mucosa, bovine lung)
- Sulphated GAGs (glycoaminoglycans)
- Alternating glucuronic acid and N-acetyl-D-glucosamine residues
It can be used as intravenous or continuous infusion. (Cannot cross the mucosal barrier so cannot be given orally)
Describe the UH Mechanism of Action
Unfractionated heparin binds to and increases activity of antithrombin III.
Antithrombin III inactivates:
- Thrombin (IIa) and factor Xa
- And also IXa, XIa, XIIa
It requires constant APTT monitoring (blood test) (tells you whether you have achieved the desired anticoagulant effect, underdosed or overdosed)
- Therapeutic range: 50-80 secs
Describe the UH Pharmacokinetics
Unfractionated heparin must be given parenterally (IV, SC). This is because it has negative charge, so no GI absorption
It has rapid onset and offset of action (IV)
- Short half-life (<60 min)
- Reticulo-endothelial uptake
- Cleared by reticulo-endothelial system, as compared to LMWH which is cleared renally
- Therefore, one of UH’s biggest advantage is that you can rapidly turn it on and off
It has variable bioavailability
- Unpredictable binding to cells and plasma proteins
- Platelets (heparin neutralizing protein); endothelial cells
- Albumin
Therefore, it needs monitoring with APTT (activated partial thromboplastin time)
- APTT in normal adult is 25-37s
- Therapeutic range is 50-80s
Describe how you would administer the UH (UH Infusion)
Loading dose is 60 units/kg (max 5000 units).
- Give bolus dose IV over 5 minutes.
Maintenance infusion commences at 12 units/kg/hr IV (max 1000 units/hr)
- Use heparin solution 100 units/mL (2500 units in 250mL saline)
- Rate of infusion varies with bodyweight
- Titrate heparin dose appropriately vs APTT
- Monitor APTT 6 hours after starting the infusion and then adjust the infusion rate according to the table.
- If already therapeutic, check next morning
Also the patient was 50kg, you’d give them 600 units per hour. About 4 hours later, you’d check the patient’s APTT. If the result was 50-80s, then you’d keep giving them the same dose.
What are some disadvantages of UH?
UH Disadvantages
It is 1) difficult, 2) complicated, 3) time consuming. 4) It requires multiple blood tests and 5) variable APTT control.
It has 6) multiple adverse effects
- Bruising/bleeding sites (can be reversed), i.e. intracranial, injection sites, GI loss, epistaxis.
-
Thrombocytopenia (Heparin Induced Thrombocytopenia - HIT)
- Check platelets every 2 days
- Autoimmune phenomenon (usually 1-2 weeks of Rx); lab assay for these antibodies
- May bleed or get serious thromboses
- Stop heparin
- Osteoporosis (long term use)
If someone on UF Heparin Therapy starts bleeding, what should you do?
Reversal of UH Therapy
- Stop heparin
- If actively bleeding, give protamine sulphate
- Dissociates heparin from antithrombin III
- Irreversibly bind to heparin
- Little effect on LMWH
- Monitor APTT
Describe the Mechanism of Action of Low Molecular Weight Heparin
LMWH has smaller chains (usually 4-5 kDaltons). Generated by chemical or enzymatic depolymerisation of UH.
- LMWH have unique sequence to bind to antithrombin III
- But Do not inactivate thrombin (IIa)
- Affects factor Xa specifically
It has reliable dose-effect relationship (bioavailability much more predictable; weight-dependent dose; given subcutaneously)
No monitoring is required (can measure Xa activity, but mostly unnecessary)
What are some advantages of LMWH?
- LMWH is better absorbed so higher bioavailability.
- It d_oes not bind to plasma proteins_, macrophages or endothelial cells
- Longer biological half-life
- More predictable dose-response
- No monitoring required
- It is given subcutaneously (done in hospital or at home)
- Lower risks of thrombocytopenia, bleeding, osteoporosis
- Safety and use during pregnancy is not evaluated
What are some disadvantages of LMWH?
- LMWH cannot be monitored by APTT
- It is not fully reversed by protamine
- Use with caution in r_enal failure_
- Dose reduction if eGFR <30
- LMWH is cleared renally, whereas UH is cleared by reticulo-endothelial system
What are the uses of UH vs LMWH?
Unfractionated Heparin
- STEMI (PCI)
- Initial DVT/PE Rx
- Short term warfarin alternative
Low Molecular Weight Heparin
- Non STEMI; STEMI (fibrinolysis)
- Initial DVT/PE Rx diagnosis
- Warfarin alternative
- Most commonly used heparin
Describe the Administration of LMWH
It is usually subcutaneous (sc) administration (o.d./b.d.), usually use enoxaparin
- Prophylaxis: 20-40mg od sc (for people at high risk of DVT/PE)
- Don’t need to memorise the doses.
- Treatment: 1mg/kg bd sc (DVT/PE)
Name the type of LMWH we usually use in NZ?
enoxaparin
Describe the Mechanism of Action of Wafarin(oral)
Vitamin K is required by the liver when synthesizing clotting factors II, VII, IX and X (vitamin K dependent proteins)
- Warfarin antagonises this process by inhibiting the oscillation between oxidized and reduced vitamin K.
- Therefore, warfarin inhibit synthesis of coagulation factors.
Warfarin has s_low onset of anticoagulation action_
- Because even if the liver is inhibited from synthesizing more factors, there are already some circulating
- Time taken for anticoagulant effect is dependent on the half-life of the clotting factors (which is a few days)
- That’s why when someone presents with DVT or PE you don’t give them warfarin first but instead LMWH because of its fast onset of action (maintain heparin infusion until you know the warfarin is taking full anticoagulant effect)
*Note that the anticoagulants don’t dissolve the blood clot. It just prevents its propogation. (gives time for our own plasmins etc. to dissolve it)
Describe the Duration of Anticoagulation use.
Anticoagulants mentioned so far don’t actually dissolve the blood clot, _they prevent existing clots from extending and breaking of_f to form an embolus. It is the body’s own plasmin and proteases that break down the clots over time.
Therefore, duration of anticoagulation _depends on how long proteases and plasmin tak_e to break down the clot
*See pic
How do you monitor Wafarin?
IND = Patient’s Prothrombin time/Mean normal PT time
Usually you’re aiming for INR of 2-3
What are some drug interactions with wafarin?
- Majority of drugs increase anticoagulant effect (increase INR), hence cytochrome P450 inhibitors (slower metabolism)
- But some drugs decrease effect (decrease INR), hence cytochrome P450 inducers (faster metabolism)
