Anticoagulants Flashcards
unfractionated heparin - description, half life, administration, mechanism explaining binding, does it need monitoring?
45 polysaccharide unit mixture
fast onset of action, T1/2 = 30 mins at low dose
typically iv bolus and infusions, sc for prophylaxis with a much lower bioavailability
binds to antithrombin (ATIII) causing conformational change and increasing the activity of ATIII. to catalyse inhibition of thrombin (IIa), heparin needs to simultaneously binds ATIII and IIa.
to inhibit Xa, only requires ATIII binding
requires monitoring with aPTT
low molecular weight heparin - names, description, administration, bioavailability, mechanism, and synthetic drug name and mechanism
dalteparin, enoxaparin
15 polysaccharide, almost always sc, bioavailability >90% and has a longer half life of 2hrs
more predictable response as it does not bind to endothelial cells, plasma proteins and macrophaes
does not inactivate thrombin IIa
inhibition of Xa specifically by enhancing ATIII activity
fondaparinux - synthetic pentasaccharide selectively inhibits Xa by binding to ATIII, s.c. T1/2 18hrs
what are the general pharmacokinetics of heparins?
large negatively charged molecules - poor GI absorption so given parenterally
what are the indications for use of heparins?
prevention of VTE, preoperative prophylaxis with LMWH, during pregnancy, acute coronary syndromes or post STEMI/NSTEMI
what are the adverse reactions of heparins?
- bruising and bleeding
- hepatic and renal impairment
- heparin induced thrombocytopenia, more common in UFH
- it is an autoimmune response 2-14 days after initiation of drug, antibodies to heparin-platelet-factor-4-complex develop and causes reduction in platelets, and can also lead to thrombosis as more platelets activated by damaged endothelium
- hyperkalaemia due to inhibition of aldosterone
- osteoporosis in long term use, higher risk with UFH
what is used to monitor heparin, which requires more monitoring, what is used to reverse treatment and the mechanism of this?
aPTT - activated partial thromboplastin time, LMWH requires less monitoring as much more predictable
protamine sulphate - forms an inactive complex with heparin, it dissociates her pain from ATIII, can cause bleeding and amount given guided by heparin dose
- greater effect with UFH>LMWH>fondaparinux
vitamin k antagonist - name, mechanism, half life
warfarin
inhibits activation of vitamin k dependent clotting factors, inhibits conversion of vitamin k to active rescued form - competitive inhibition of VKOR
- clotting factors II,VII,IX,X all require vit k as cofactor
- delay in onset of action as circulating active clotting factors present for several days
- T1/2 = 36-48 hrs
what are the indications for the use of warfarin?
VTE (PE, DVT, secondary prevention, superficial vein thrombosis), atrial fibrillation with high risk of stroke, heart valve replacement, generally used in longer term anticoagulation, slow onset of action likely to require heparin cover if anticoagulation needed immediately
what are the pharmacokinetics of warfarin?
- good GI absorption, 95% bioavailability
- functional CYP2C9 polymorphisms contribute to variability
- plasma conc does not correlate directly with clinical effect
- warfarin is a mixture of 2 enantiomers which have different potencies
- crosses placenta so avoided in 1st and 3rd trimersters
what are some adverse drug reactions of warfarin and what is the most effective antidote?
bleeding- epistaxis and spontaneous retroperitoneal bleeding, antidote = vitamin k1 and prothrombin complex concentrate IV
what are some drug-drug interactions of warfarin?
inhibition of hepatic metabolism esp CYP2C9 - amiodarone, clopidogrel, intoxicating dose of alcohol, quinolone, metronidazole
reduced vit k by eliminating gut bacteria involved in production - cephalosporin
displacement of warfarin from albumin - NSAIDs and drugs that decrease GI abs. of vitamin K
acceleration of warfarin metabolism - barbiturates, phenytoin, rifampin, st johns wort (likely decreases INR)
what is used to monitor warfarin?
INR - clotting time against standard
- factor VII most sensitive to vitamin K deficiency so used in prothrombin time
DOACs - names, mechanisms
apixaban, edoxaban, rivaroxaban
- direct oral anticoagulants, inhibit both free Xa and that bound with ATIII, do not direct affect thrombin (IIa) - hepatic metabolism and scripted partly by kidneys
T1/2 around 10 hours
dabigatran - selective direct IIa thrombin inhibitor, both circulating and thrombus bound IIa
T1/2 - 9 hours
what are some positives to DOAC use?
less frequent interactions than warfarin but affected by CYP inducers and inhibitors
- plasma conc decreased by carbamazepine, phenytoin, barbiturates
- plasma conc increased by macroclides
- lower intracranial bleed risk
where is dabigatran use contraindicated?
low creatinine clearance
