S10) Anti-Coagulant and Anti-Platelet Therapy Flashcards
What is warfarin’s mechanism of action?
Warfarin inhibits the production of Vitamin K dependent clotting factors by stopping the conversion of Vit K to active reduced form
→ half life is 26-48 hours
Warfarin is the preferred drug choice for long term anti-coagulation.
How is warfarin administered?
Orally – due to good GI absorption
Briefly, describe the pharmacokinetics of warfarin
- Slow onset of action (needs Heparin initially)
- Slow offset (t1/2 48 hrs)
- Heavily protein bound
How is warfarin metabolised and what is the clinical significance of this?
Mixed function Oxidase cytochrome p450 system:
- Caution with liver disease
- Caution if used with drugs that affect p450 system
what is INR
→ international normalised ratio - clotting time against a standard = comparable
normally 2.5
if 3-3.5 = recurrent DVT, PE in patients recieving anti-coagulants
Warfarin crosses the placenta.
What is the clinical signicance of this?
- Do not give in 1st Trimester → Teratogenic
- Do not give in 3rd Trimester → Brain Haem
How can one monitor the effects of warfarin?
- Extrinsic Pathway Factors
- Prothrombin Time
- INR (International Normalised Ratio)
Provide some examples of drugs which potentiate the actions of warfarin
- Amiodarone, quinolone, metronidazole – inhibit hepatic metabolism and CYP2C9
- Aspirin – inhibit platelet function
- Cephalosporin antibiotics – reduce Vitamin K from gut bacteria
Provide some examples of drugs which inhibit the actions of warfarin
Inducing hepatic enzymes, thus increasing metabolism of warfarin:
- Anti-epileptics (except Na+ valproate)
- Rifampicin
- St Johns Wort
What are the usual indications for warfarin?
- DVT (3-6 months)
- PE (6 Months)
- Atrial fibrillation (Until risk > benefit)
– venous thromboembolism
– superficial vein thrombosis
– longer term use over heparins
–
What are the adverse drug reactions of warfarin?
- Teratogenic
- Bleeding/bruising (intracranial, epistaxis, injection, GI loss)
warfarin drug-drug interactions
→ reduce vit K by eliminating gut bacteria (Cephalosporin antibiotics)
→ displacement of warfarin from albumin , NSAIDS and drugs that decrease GI absorbing K = increase INR (more anti-coagulated)
→ acceleration of warfarin metabolism, Barbiturates, phenytoin, rifampicin = decrease INR (less anticoagulated)
In seven steps, describe the clinical approach one takes before prescribing warfarin
⇒ Indication
⇒ PMH e.g PUD, SAH, bleeding disorder
⇒ Medications (interactions)
⇒ Age, Mobility (blood tests and clinics)
⇒ Review blood tests (LFTs, Plt, INR),
⇒ Consider loading dose and heparin cover
⇒ Prescribe
How does one manage a patient on warfarin with increasing INR levels of 3.0 < INR < 6.0 (no bleeding)?
- Reduce warfarin dose and stop
- Restart warfarin when INR < 5.0
How does one manage a patient on warfarin with increasing INR levels of 6.0 < INR < 8.0 (no bleeding / minor bleeding)?
- Stop warfarin
- Restart warfarin when INR < 5.0
How does one manage a patient on warfarin with increasing INR levels of INR > 8.0 (no bleeding / minor bleeding)?
- Stop warfarin
- Restart warfarin when INR < 5.0
- If other risk factors for bleeding, give patient oral Vitamin K
How does one manage a patient on warfarin who experiences major bleeding?
- Stop warfarin
- Give prothrombin complex
- Give oral Vitamin K
Describe the mechanism of action of heparin
- Activate Anti-Thrombin III (ATIII) via unique pentasaccharide sequence
- Deactivates thrombin, Factor Xa, IIa, IXa, (probably VIIa, XIa, XIIa)
Identify and describe the two different types of heparin molecules
- Unfractionated Heparin (intravenous for continuous or subcutaneous for prophylaxis) 20 kDa
- Low molecular weight Heparins (subcutaneous) 3-4 kDa
Compare and contrast the varying effects of LMW heparin and Unfractionated heparin on Factor Xa and thrombin
Compare and contrast UFH and LMWH based on the following factors:
- Dose-response
- Bio-availability
- Action
- Administration
- Initiation
pharmacokinetic of warfarin
→ good GI absorption, taken orally = 95% bioavailability
→ CYP2C9 polymorphism = significant inter-individual variability
→ mixture of two enantiomers - R and S which have different potencies and so are metabolised differently
How is heparin administered?
Parenterally – due to poor GI absorption
what produces heparins
mast cells and vascular endothelium
what are unfractioned heparins
→ fast onset of action,
→ IV bolus and infusion (low bioavailability)
→ binding to antithrombin III = confrontational change and increased activity of antithrombin III
→ binds to ATIII and IIA to catalyse inhibition of thrombin IIa
→ Xa inhibition only needs ATIII binding
what are some examples of low molecular weight heparins
dalteparin
enoxaparin
low molecular weight heparins
→ given s.c
→ long half life and bioavailability
→ predictable response as it doesn’t bind to endothelial cells, plasma proteins, macrophages
→ don’t activate thrombin IIa
→ inhibition of Xa
what is fondaparinux an example of and its role
→ low molecular weight heparin
→ synthetic pentasaccharide selectively inhibiting Xa by enhancing ATIII
comparison of unfractioned heparins and low molecular weight heparins
Briefly, describe the pharmacokinetics of heparin
- Rapid onset of action (heparin cover)
- Rapid offset of action
Describe the uses of heparin
- Prevention of thrombo-embolism during operation in those normally on warfarin (stopped for surgery)
- Heparin cover for DVT/PE and AF
- Pregnancy in place of warfarin
- Reduces recurrence/extension of acute coronary syndromes
Identify some adverse drug reactions of heparin
- Bruising/bleeding sites (intracranial, GI loss, epistaxis, injection sites)
- Osteoporosis
- Thrombocytopenia
→ hyperkalemia (inhibition of aldosterone secretion)
→ avoid giving to people with clotting disorders and renal impairment
Describe the reversal therapy for heparin (what is used, how?)
Protamine sulphate:
- Dissociates heparin from anti-thrombin III
- Irreversible binding to heparin
- Used for major bleeding, allergy / anaphylaxis
Identify some anti-platelet drugs and their mechanism of action
- Aspirin – COX-1 (cyclo-oxegenase) inhibition
- Dipyridamole – Phosphodiesterase Inhibitors
- Clopidogrel – Inhibit ADP dependent aggregation
- Glycoprotein IIb / IIIa Inhibitors – decreases platelet crosslinking by fibrinogen
Vitamin K antagonist
Warfarin
what is prostacyclin (PGI2)
→ produced by endothelial cells that inhibit platelet aggregation
→ bind to platelet receptors and reduce levels of cAMP
→ this reduces calcium levels
→ reduction in platelet aggregation
how does aspirin work
→ COX-1 inhibitor
(COX-1 produces arachidonic acid that forms thromboxane)
→ irreversible / high doses can also inhibit PGI2
however, will not completely inhibit platelet aggregation as there are other aggregating agents
who to avoid giving aspirin to
→ reyers syndrome (increase of pressure in brain → aspirin can worsen this)
→ hypersensitivity
→ 3rd trimester of pregnancy can cause premature closing of ductus arteriosus (shunt between pulmonary artery and the aorta)
which drugs should you avoid giving aspirin with
- other anti-platelet and anticoagulants
why does the anti-platelet effect last the lifespan of a platelet
because after 7-10 days the platelet function will recover
what are some other reasons to prescribe aspirin
→ AF patients past stroke
→ secondary prevention of Transient ischemic attacks (mini stroke)
→ secondary prevention Acute coronary syndromes
-< NSTEMI/STEMI → chewable is the best because It increases absorption
how do ADP receptor antagonists work and what are some examples?
→ inhibit binding of ADP→P2y12 receptors so inhibit activation of GPIIb/IIIa receptors
→ Clopidogrel
→ prasugrel
→ ticagrelor
how do ADP receptor antagonists drugs slightly different from each other
- Clopidogrel and prasugrel are irreversible inhibitors of P2Y12 they are prodrug
- clopidogrel has a slow onset of action without loading dose
- ticagrelor and prasugrel have longer acting
what are some side effects of ADP receptor antagonists
- bleeding especially with hepatic or renal failure
- GI upset and rarely thrombocytopenia
drug interactions with ADP receptor antagonists
- clopidogrel requires CYPs (cytochrome p450)for activation as it is a pro drug. This is produced in the liver
- SO must avoid CYP inhibitors (erythromycin) or if someone has hepatic failure
what are some other uses of ADP receptor antagonists
- ischemic stroke (TIA)
- N/STEMI
phospodiesterase inhibitors
eg: Dipyridamole
→ inhibits cellular uptake of adenosine so increased adenosine → inhibit platelet aggregation via A2 receptor
→ Also prevent cAMP degradation so inhibit GP11b/IIIa
must avoid giving with adenosine
glycoprotein IIb/IIIa inhibitors
- abciximab (IV)
- blocks binding of fibrinogen and and vonWillebrand factor
- terminates the final step of platelet formation
- can cause bleeding and should be careful to use =with other anti-paletelt and anti-coagulating agents
what is PCI (percutaneous coronary intervention)
→ using stent to remove plaque
→ normally go for this method if they have a STEMI
but it can cause repercussion injury where there a damaging oxidative and calcium species can come in
treatment if someone has an ACS
- PCI
- when heamodynamically stable:
- ACEi, B blockers, dual anti-platelet therapy
- statin
what is tranexamic acid used for
→ treats excessive blood loss after major trauma
→ inhibits fibrinolysis by inhibiting plasmin
according to the nice guidelines what is the medication that should be used as secondary prevention if someone has just had a TIA
Clopidogrel inhibits ADP binding to platelet receptors
DOACs examples
Direct acting oral anticoagulants:
→ apixaban
→ edoxaban
→ rivaroxaban
how do DOACs work
→ Direct Xa: inhibit free Xa bound with ATIII (dint directly effect thrombin IIa
→ Direct IIa: dabigatran → selective direct competitive thrombin inhibitor
→ need more monitoring over warfarin
adverse effects of DOACs, warnings and drug interactions
→ bleeding, skin reactions
→ avoid in pregnancy and breastfeeding: contradicted in low creatinine clearance. Avoid in people with severe hepatic disease
→ has less frequent interactions that warfarin but affect CYP inhibitors and inducers:
– reduced by carbamazepine, phenytoin
– increased by macrolides
