Anti-Coagulants Flashcards
1
Q
Describe Virchows Triad and potential factors causing abnormalities
A
- Abnormality of blood constituents - hypercoagulability
- Genetic - protein C & S deficiency, factor V Leiden
- Acquired - smoking, malignancy, OCP, prosthetic heart valves
- Abnormality of vessel wall - endothelial damage
- Atheroma - MI
- Hypertension
- Toxins - cigarette, homocysteine
- Abnormality of blood flow - stasis
- Immobility - DVT
- Cardiac abnormality - AF, mitral valve disease, post MI
- Immobility - DVT
2
Q
Recognize the sites at which anticlotting agents act
A
- Warfarin reduces factor II, VII, IV, X
- Heparin converted to heparin antithrombin complex and inhibits multiple clotting factors including factor Xa and IIa
- Low molecular weight heparin inhibits factor Xa
- Antiplatelet drugs such as aspirin prevent platelet plug formation by affecting thromboxane A2 and GP IIb/IIIa
3
Q
Describe the mechanism of warfarin
A
- Warfarin inhibits production of vitamin K dependent clotting factors - factor II, VII, IX, X
- Vitamin K needed to carboxylate these clotting factors
- Warfarin blocks recycling of vitamin K by acting as competitive inhibitors (coumarins)
- Clotting factors which have already been activated are unaffected and will decay
4
Q
Describe the main therapeutic uses of warfarin
A
- DVT, PE, AF
- Heart valve replacement
- Prophylaxis in heart attack, stroke
5
Q
Describe the route of administration and onset/offset of action of warfarin
A
- Good GI absorption - give orally
- Slow onset of action - need heparin to cover initially
- Slow offset - half life ~ 48 hours but variable - need to monitor INR to measure effect
- Need to stop 3 days before surgery - give time for liver to synthesize new clotting factors
6
Q
Describe the distribution and metabolism of warfarin
A
- Heavily protein bound - drug interactions
- Hepatic metabolism - cytochrome P450 system, caution with liver disease
7
Q
Describe the significance of warfarin in pregnancy
A
- Crosses placenta - do not give in first trimester - teratogenic
- Do not give in third trimester - deformity in head of baby leading to brain haemorrhage
8
Q
Define INR
A
- INR is a standardised prothrombin time
- Measures the time it takes for coagulation to occur for patients taking oral anticoagulant medication
9
Q
Describe the general dosing regime of warfarin
A
- Loading dose of 10mg given and further doses given depending on INR
- DVT, PE, AF patients INR ratio kept between 2.0-3.0
- Conditions likely to have increased clotting have INR kept between 2.5-4.5
10
Q
Describe the important effects of DDI on warfarin
A
- Majority of DDIs increase anticoagulant effect of warfarin - will increase INR
- Inhibit hepatic metabolism - drugs that affect CYP450, increasing concentration of warfarin and enhancing its anticoagulant effect
- Inhibit platelet function
- Aspirin - block both platelets and clotting cascade
- Reduce vitamin K from gut bacteria
- Cephalosporin antibiotics - block vitamin K enhances warfarin effect
- Some drugs inhibit anticoagulant effect of warfarin
- Antiepileptics, rifampicin, St Johns Wort
- Induce hepatic enzymes therefore increasing metabolism of warfarin - decrease INR
- Antiepileptics, rifampicin, St Johns Wort
11
Q
Describe the main ADRs of warfarin
A
- An INR above 4.5 has a high risk of bleeding - withhold warfarin for 1-2 days and review
- Bleeding/bruising
- Intracranial (rare but serious), epistaxis, injection sites, GI loss (anaemia)
- Teratogenic - crosses placenta
12
Q
With reference to INR< explain the steps in reversing warfarin action
A
- If INR > 4,5, withhold warfarin for 1-2 days and review
- If INR > 8.0, give vitamin K by slow IV injection to reverse warfarin action
- Also give larger dose vitamin K if haemorrhage occurs
- Parenteral vitamin K takes 2-3 days to synthesize clotting factors and reverse warfarin effect
- If vitamin K given, then patient cannot be anticoagulated for a month
- Give fresh frozen plasma (clotting factors given directly) if fast reversal needed
- When stopping or reversing warfarin, consider effects on bleeding and INR
13
Q
Describe the mechanism of heparin
A
- Both groups activate anti-thrombin III complex
- Xa inhibition by AT III needs only heparin to bind to AT III, thus both groups inhibit it
- To catalyse inhibition of IIa by AT III, heparin needs to simultaneously bind to IIa and AT III
- Unfractionated heparin is large enough for this, thus it inhibits factor Xa and IIa
- LMWH not large enough, thus only inhibits factor Xa
14
Q
Describe the route of administration of initiation of UFH and LMWH
A
- UFH given IV through bolus and then IV infusion as 5 half lives needed to reach steady state
- LMWH given subcutaneous once/twice a day
15
Q
Describe the dose-response, bioavailability and monitoring of UFH vs LMWH
A
- UFH non-linear dose-response while LMWH predictable response
- UFH bioavailability variable due to unpredictable binding to cells and proteins while LMWH predictable due to less binding to macrophages and endothelium
- UFH needs monitoring with APTT while LMWH does not need monitoring
16
Q
Describe the uses of heparin
A
- Prevention of thrombo-embolism
- Peri-operative - low molecular weight heparin low dose
- Immobility - chronic heart disease, frail, unwell patient
- Used to cover for risk of thrombosis around times of operation in those normally on warfarin but who have stopped it for the surgery
- Quick offset time allows its cessation if bleeding
- DVT/PE and AF
- Administered prior to warfarin
- LMWH often used unless fine control required (LMWH does not need monitoring thus heparin levels difficult to control)
- Acute coronary syndromes
- Reduces recurrence/extension of coronary artery thrombosis
- MI, unstable angina - LMWH given
- Pregnancy - can be used cautiously in pregnancy to replace warfarin
17
Q
Describe the main ADRs of heparin
A
- Bruising/bleeding sites - intracranial, injection sites, GI loss, epistaxis
- Thrombocytopenia - leads to depletion of platelets and thus bleeding or serious thromboses can form
- Osteoporosis - long term
18
Q
Describe how heparin can be reversed
A
- Protamine sulphate given to neutralize negative charge on heparin
- Dissociates heparin from anti-thrombin III
- Irreversible binding to heparin
- Overdose causes increased bleeding - APTT needs to be monitored
19
Q
Other than heparin and warfarin, state the action of newer ACAs
A
- Selective factor Xa inhibitors
- Direct thrombin inhibitors
20
Q
List 4 antiplatelet drugs
A
- Aspirin
- Glycoprotein IIb/IIIa inihibitors
- Dipyridamole
- Clopidogrel
21
Q
Describe the mechanism of aspirin
A
- Aspirin - COX-1 inhibition prevents conversion of arachidonic acid to thromboxane A2
- Need to generate new platelets if coagulation needed as aspirin irreversible
22
Q
Describe the mechanism and uses of glycoprotein IIb/IIIa inhibitors
A
- Decreases platelet crosslinking by fibrinogen and causes platelet aggregates to break apart
- Used in high risk acute coronary syndrome and post PCI
- Increases bleeding complications but decreases acute thrombosis and re-stenosis
- Lasts long time in body
23
Q
Describe the mechanism and uses of dipyridamole
A
- Phosphodiesterase inhibitors
- Prevent the inactivation of cAMP and thus reduces platelet aggregation
- Prostaglandin further increases cAMP
- Positive inotrope and vasodilatory (flushes and headaches)
- Secondary prevention of stroke
24
Q
Describe the mechanism and uses of clopidogrel
A
- ADP antagonists
- By blocking ADP receptor, leads to a build up of cAMP which reduces platelet aggregation
- Used with aspirin in acute coronary syndrome and PCI
25
Q
Give examples of thrombolytic drugs
A
- Clot busters used in MI, stroke and PE
- Tissue plasminogen activators - alteplase, retaplase
- Streptokinase - less preferred compared to tissue plasminogen activators as more side effects
