Anticoagulant drugs Flashcards
What are the types of disease that you’d use anti-platelets and anticoagulants for?
Coronary artery disease
Cerebrovascular disease
Peripheral vascular disease
What are the types of thromboembolic diseases that you’d just use anticoagulants for?
Atrial fibrillation
Venous thrombi-embolism (DVT, PE)
Prosthetic cardiac valves (metal)
What is virchows triad?
hyper coagulability, endothelial damage, stasis
Heparin, uses
Acute coronary syndromes Thromboembolism (prophylaxis and treatment) Venous: DVT and PE Arterial AF Warfarin replacement - pregnancy
Heparin molecules - describe
linear mucopolysaccharide chains MW very variable: 3000 - 40000 Unfracitionated heparin (IV, continuous infusion)
Unfractionated heparin
- what
- MoA
- Monitoring?
Mix of variable length heparin chains - pig intestine mucosa and bovine lung MoA - binds to and increases activity of anti thrombin III antithrombin III inactivates - thrombin (IIa) and factor Xa - and also IXa, XIa, XIIa requires APTT monitoring (blood test)
UH - pharmacokinetics
Must be given parentally (IV, SC) - negative charge, no GI absorption Rapid onset and offset of action - Short half life (<60min) - Reticuloendothelial uptake Variable bioavailability due to unpredictable binding to cells and plasma proteins - platelets (heparin neutralising protein); endothelial cells - Albumin - Needs monitoring with APTT
Unfractionated heparin, what is the therapeutic range measured on APTT
Adult reference range 25-37sec
Therapeutic range 50-80sec
Unfractionated heparin
- loading dose
- maintenance infusion
LD: - 60 units/kg (max 5000units) - give bolus dose iV - over 5 mins MD - Heparin solution 100units/ml, 25000units in 250ml saline k
commence at 12 units / kg/ hr max
titrate heparin dose appropriately vs APTT
Disadvantages of unfractionated heparin therapy
difficult complicated time consuming blood tests variable APTT control
Adverse effects of unfactionated heparin use
brusing/ bleeding
- intracranial
- Injection site
- GI loss
- Epistaxis
Thrombocytopenia (HIT)
- check platelets every 2 days
- Autoimmune phenomenon (usually 1-2 weeks of Rx)
- May bleed or get serious thromboses
- Lab assay for these antibodies
- Stop heparin
Osteoporosis with long term use
Reversal of UF heparin therapy
- Stop heparin
- If actively bleeding give protamine
- Monitor APTT if unfractionated heparin
Protamine sulphate?
- dissociates heparin from antithrombin III
- Irreversible binding to heparin
- Little effect on LMWH
About LMWH
Much more predictable in MOA and bioavailability
Smaller chains usually 4-5 Kdaltons
- generated by chemical or enzymatic depolymerisation of unfractionated heparin
Like UH have unique sequence to bind to antithrombin III
- Doesn’t inactivate thrombin IIa
- Affects factor Xa specifically
Reliable dose effect relationship
No monitoring required can measure factor Xa activity
LMWH - advantages
Better absorbed - higher bioavailability
Doesn’t bind to plasma proteins, macrophages or endothelial cells
- Loger biological half life
- More predictable dose response
- No monitoring required
Can be given Sc in an outpatient setting (teach patient how to give the dose themselves)
Lower risk of thrombocytopenia and bleeding
Safety and use during pregnancy not evaluated
LMWH vs unfracitonated heparin
pros and cons
pros - improved Pk especially SC route - monitoring not usually required - less thrombocytopenia - less osteoporosis Cons - Cannot be monitored by APTT - not fully reversed by protamine - care in renal failure (UF was cleared by the reticular endothelial system, LMWH cleared by the kidneys)
LMWH admin
Subcutaneous admin (OD/BD)
- Enoxiparin
Prophylaxis: 20-40mg od sc
Treatment 1mg/kg bd sc (reduce of low GFR)
treatment for PE/DVT
- initially LMWH
- Give warfarin
- Continue LMWH for 5-7 days until INR therapeutic
Warfarin MoA
Vit K required by the liver to synthesise various clotting factors
slow onset of anticoagulant action, as half life of coat factors: VII, IX, X and II is a few days, therefore cant be used for immediate DVT/ PE treatment
Specifically prevents the osculation between oxidised and reduced vitamin K
Uses of warfarin
Treatment of venous or arterial thrombosis
- DVT/PE
- Mural thrombus (post anterior MI) reduce risk of embolisation
Prevention of venous or arterial thromboembolisaiton
- mechanical heart valves
- AF (risk of systemic emboli)
Risk stratification for warfarin treatment
Treatment is 3-6 months for DVT, 6 months for PE
Lifelong if > 1 episode
lifelong - mechanical valves/ AF
Warfarin admin and metabolism
oral admin, OD, 99% bound to plasma protein
Completely absorbed - crosses placenta
Metabolised by the liver cytochrome P450, so lots of drug interactions
- oxidation
- Glucuronidaiton
- Enteroheptic cycling
t1/2 = 36 hours
Warfarin GI absorption
Oral preparation High bio availability taken orally Rapid absorption Pharmacological activity takes days - Long effective half life - Awaiting degradation of active factors Factor II t1/2 = 60 hours
Warfarin unwarranted effects
Haemorrhage (e.g. in older age groups, people with cerebrovascular disease) - intracranial - GI Teratogenic - First trimester (very bad for babe)
Relative contraindications to warfarin therapy
Pregnancy Situations where the risk of haemorrhage is greater than the potential clinical benefits of therapy - Uncontrolled alcohol/ drug abuse - Unsupervised dementia / psychosis - Falls - poor concordance / insight
INR?
Patients PT in secs / Mean normal PT in secs
Individual variation in warfarin metabolism caused by
Absorption: - Diarrhea / vomiting metabolism - Liver disease Nutrition / dietary (vit K) Co exisiting illness
Examples of drugs potentiating warfarin
Amiodarone
Antibiotics e.g. erythromycin
Anti- fungals e.g. fluconazole
Drugs inhibiting warfarin
Azathioprine
Barbiturates
Carbamezapine
Management of Increased INR
life threatening bleeding: stop warfarin, give FFP and blood
IV and vit K 1-10mg, vit K has long action on reducing warfarin effect but slow onset
Oral vit K
IV beriplex
- prothrombin complex concentrate
- Contains factor II, VII, IX, X protein C
For less lie threatening cases, withhold warfarin re check INR, lower dosage
Hirudin
Derived from leech
Thrombin inhibitor
Antithrombin II indépendant
Little effect on platelets
Dabigatran
(dabigatran etexilate) - prodrug - capsule with tartaric acid - Gut, plasma, liver esterases Competitive reversible inhibitor
Idracuzimab
intravenous monoclonal antibody
for atrial fibrillation
VTE prevention and treatment
cant use for mechanical valves
