10. Anticoagulants PHARM Flashcards
what accounts for the highest number of adverse events of all drug classes?
anticoagulants!
what are the qualities of an arterial thrombus?
- occurs in association with a vascular disease
- occurs under high flow
- platelet aggregates, bound by fibrin
- causes tissue ischemia by obstructung flow or embolizing to distal circ
what are the qualities of a venous thrombus?
- lower limbs, generally
- conditions of low flow, stasis
- composed of RBCs and fibrin, few platelets
- obstructed venous return, inflammation, PE.
indications for anticoagulation?
- primary prevention of thrombosis
- secondary prevention (prevent a second clot)
- treatment of acute thrombosis
what are some primary causes of venous thrombosis?
hospitalization, surgery, immobilization, cancer
what are some primary causes of arterial thrombosis?
stroke in afib, MCI, mechanical heart valves
the choice of what anticoagulant we use depends on what?
the mechanism of the thrombus formation
if a thrombus forms by afib, is it more like an arterial or venous clot?
more like a venous, because it is due to stasis
arterial thrombosis: caused by vasc damage? what is mechanism? clot composition? appearance?
caused by vasc damage, mech = shear stress, composition = platelets and fibrin, apearance iws white
venous thrombosis: caused by vasc damage? what is mechanism? clot composition? appearance?
not caused by vasc damage, mech = stasis, composed of RBC and fibrin, appearance is red
treatment class for arterial thrombi?
antiplatelet agents
treatment class for venous thrombi?
anticoagulants
what is the main role of antiplatelet agents?
to interrupt formation of the primary platelet plug.
what are the anti-platelet agents?
aspirin, clopidogrel, prasugrel, ticagrelor, dipyridimole, GPIIb/IIIa receptor antagonists
what do the antiplatelet agents change in terms of lab values?
they prolong the bleeding time/PFA-100
clopidogrel, prasugrel, ticagrelor: what is their mechanism?
antagonize the ADP P2Y12 receptor
what is aspirin’s mechanism of action?
irreversibly inhibits COX, which converts arachidonic acid into TXA2 and allows platelet aggregation.
what is arachadonic acid? where does it come from?
from platelets when they are activated. converted to thromboxane As (TXA2). TXA2 then allows platelet aggregation.
what is half life for ASA? how long does the effect last?
half life is 20 min, but effect lasts for lifespan of platelets.
how long in advance do we discontinue ASA for restoration of platelet function?
7-10 days
does ASA affect platelet adhesion?
no, just aggregation
ASA: main side effects?
GI, dose-related.
in what patients will ASA increase bleeding tendency?
pts with bleeding disorders, the elderly
not associated with major bleeding in pts with normal hemostasis at baseline
what are ibuprofen and naproxen? what class, what is thei main function?
NSAIDS
reversible inhibition of COX.
with NSAIDS, how quickly does platelet function return?
function is restored when drug is cleared.
how long in advance do we discontinue ibuprofen for restoration of platelet function? what about naproxen?
ibuprofen: 1-2 dyas
naproxen: several days
ibuprofen: what class? what is half-life, peak effect?
NSAID
half life is 2 hrs, peak effect 1-2 h
naproxen: what class? what is half-life?
NSAID
half life is 12-17 h
ASA: indications for use in antithrombosis?
mainly prevention of primary and secondary ARTERIAL thrombosis
not generally great for venous thromboembolism, though indicated for some surgeries like hip fracture.
what is the difference between antiplatelet and antithrombotic agents?
antiplatelets are specifically antiplatelet: the antithrombotics/anticoagulants inhibit the coagulation cascade
what are some P2Y12 receptor antagonists?
clopidogrel, prasugrel, ticagrelor
what is the mechanism in which the P2Y12 receptor participates?
damaged endothelium secretes ADP, which binds to P2Y12 receptor on platelets. platelets express GpII/bIII receptor in response.
clopidogrel: is it a drug or pro-drug?
prodrug
what are indicated uses of clopidogrel?
secondary prevention of arterial thrombosis, prevention of coronary stent thrombosis (with ASA)
Clopidogrel: adverse effects?
similar to ASA in terms of bleeding risk
incr bleeding complications when ASA and clopidogrel are used together
risk of TTP (class effect: poorly understood)
Rash and diarrhea possible.
clopidogrel: max effect how many hours after oral dose?
4-6 hours
what metabolizes clopidogrel into the actual drug?
CYP3A4
plasugrel: is it a drug or pro-drug?
prodcug
what activates plasugrel?
CYP3a and CYP2B6
prasugrel: max effect how many hours after oral dose?
1-2 hours
prasugrel: main uses?
- management of acute coronary syndromes with percutaneous coronary interventions
- prevention of coronary stent thrombosis (with ASA)
prasugrel: adverse effects?
similar to ASA in terms of bleeding risk
incr bleeding complications when ASA and prasugrel are used together
risk of TTP (class effect: poorly understood)
incr risk of STROKE
prasugrel: contraindicated in pts with history of what?
TIA or stroke
tigagrelor: drug or prodrug?
both
ticagrelor: max effect hos long after dose?
2 hrs
ticagrelor: main uses?
prevention of thrombotic CV events in patients with acute coronary sx
Note not used for stroke
ticagrelor: adverse effects?
similar to other antiplatelet meds in terms of bleeding
dyspnea and bradycardia
gynecomastia (men)
what are the main differences in use of clopidogrel and prasugrel/ticagrelor?
- clopidogrel: used to prevent arterial thrombosis (stroke, MCI when ASA is contraindicated.
- P/T: used for acute coronary syndromes, but not stroke
of the antiplatelets, which has the widest indications?
aspirin.
what are the 3 GbIIb/IIIa receptor antagonists?
abciximab, eptifibatide, tirofiban
GbIIb/IIIa receptor antagonists: mech of action?
binds GPIIb/IIIa receptor on platelet membrane, blocks binding fibrinogen to that receptor, therefore prevents platelet aggregation.
what is the main indication for GbIIb/IIIa receptor antagonists?
prevent acute vessel closure following percutaneous coronary intervention
which GbIIb/IIIa blocker is a monoclonal antibody Fab fragment?
anciximab
hich GbIIb/IIIa blocker is a cyclic heptapeptide?
eptifibatide
hich GbIIb/IIIa blocker is a small molecule?
tirofiban
Heparin: which coag factors does it inhibit?
Xa and IIa (actually it accelerates the inhibition of those coag factors by antithrombin)
Heparin; what is it’s charge?
very negatively charged.
Heparin: why is there such variation in bioavailability?
it binds to plasma proteins, and there are states in which patients have more or less plasma proteins and heparin will be sucked up by them and be less effective. varies within a single patient.
Heparin: in what forms is it available?
subQ, IV. NOT available orally or IM
Heparin: what is the bioavailability subQ vs IV?
IV: 100% bioavailable, effect is immediate
subQ: poor bioavailability, effect 1-3 hrs.
what is the anticoag of choice in pregnancy?
heparin
heparin: how does the clearance work? half-life?
non-linear, two phases.
Phase 1: rapid: quickly cleared.
Phase 2: renal, slow
the half life is dose dependent becasue you can saturate the quick clearance, and so with a higher dose it takes longer to decay half.
heparin: what are the two dosing regimens?
mini dose, or therapeutic, adjusted full dose
describe the mini dose of heparin.
subQ, used for thromboprophylaxis, no lab monotiring needed
describe the therapeutic, full dose of heparin
IV, bolus then continuous infusion. dose adjusted according to effect on aPTT.
for treatment of acute thrombosis
heparin: why do we measure the aPTT?
will prolong both aPTT and aPT, but for lab reasons we measure the aPTT.
prolongation is proportional to anti-Xa activity.
an anti-Xa level would be more accurate, but is expensive.
what are problems with using aPTT for monitoring heparin?
things besides heparin affect teh aPTT, aPTT is only an approximation of level of hep in the blood.
AntiXa is more accurate.
is an aPTT level consistent across hosptials?
no, dependent on the reagents and equipment. location dependent.
side effects of heparin?
- bleeding (21% of patients)
- osteoporosis, mech unknown, >3 months of tx
- skin lesions
- hypoaldosteronism (rare)
what is a distastrous complicatin of heparin use? what does it look like?
heparin-induced thrombocytopenia (HIT). heparin induces an autoimmune reation against hep-PF4 antigen on platelet surface.
how can you tell if HIT is occurring?
Pt will clot despite heparin, platelet levels fall
what is the risk of HIT? what does it depend on?
depends on dose, source of heparin.
bovine: 5-10%
porcine: 1-5% depending of dose
what is the difference between heparin and LMWH?
biggest division is 18 saccharides: LMWH generally below this level, heparin (unfractionated) above this level
what is the difference in what LMWH and heparin are able to bind?
have to be at least 18 sacc long to bind thrombin (IIa). few LMWH can bind IIa, but they can all bind Xa.
heparin can bind/inhibit both
LMWH: does it have the same clearance pattern as heparin?
no, linear renal clearance. too small, does not interact with plasma proteins
what effect does LHWH have on the aPTT?
none. must use anti-Xa to monitor.
LMWH: is dosing the same as for heparin?
no, fixed weight-based dose. means we don’t have to monitor (which is good because anti-Xa is expensive)
which LMWH is preferred at DHMC: dalteparin, enoxaparin, fondaparinux, or tinsaparin?
enoxaparin.
LMWH: advantages over heparin?
fixed weight based dose subQ injection no routine lab testing require in most cases more predictable response less incidence of HIT
LMWH: disadvantages over heparin?
long half life can be a problem since there is no antidote
renal excretion, therefore use in renal insufficiency pts is difficult
fondaparinux: what is it?
synthetic pentasaccharide: extremely LMWH
fondaparinux: advantages?
once per day dosing, no HIT, no routine monitoring, as effective as heparin and other LMWHs.
fondaparinux: disadvantages?
renal excretion (use caution with renal insuff pts) no antidote (same as LMWH)
indications for heparin/LMWH?
prevention of venous and arterial thrombosis. preventing future clots from forming. NOT degrading the current clot.
if heparin/LMWH don’t degrade an established clot, what does?
endogenous fibrinolytic system
how can we reverse the heparin effect? does this work for LMWH?
antidote to heparin = protamine sulfate. works on longer chains: minimally on LMWH, not at all on fondaparinux.
problem with protamine sulfate?
it is also an anticoag, so OD will exacerbate bleeding.
warfarin: mechanism of action?
Vit K antagonist. Vit K is a cofactor for ACTIVATION of 2, 7, 9, 10, so warf inhibits the ACTIVATION of those factors.
what is the anticoag of choice for patients with renal problems?
warfarin
warfarin: how does it travel in the plasma?
protein bound, esp to albumin
how is warfarin metabolized?
in liver by P450 enzymes. clearance of drug is not affected by renal dysfunction
what can interfere with warfarin’s effect?
so many things. medications, foods high in VitK, medical conditions.
warfarin: what is the dose?
has to be individualized because there are so many conditions that alter its effect
what is the goal INR for most indications?
2-3, ideally 2.5
warfarin: what coag labs does it prolong? what is used to adjust the dose?
use PT/INR to adjust dose. prolongs both PT and aPTT
when starting warfarin, what must usually be done?
usually started along with a faster-acting anticoag due to its slow onset of action
how can warfarin induce a transient hypercoagulable state?
not sure, figure this out.
has to do with half-lives of various coag factors and their impact on the clotting cascade v the lab values
warfarin: indications?
primary and secondary prevention of venous thromboembolism
some use with arterial thrombosis: anti-stroke with afib, mechan heart valves
warfarin: side effects?
bleeding. elderly more prone.
skin necrosis. realted to transient hypercoag state at initiation of warfarin
teratogen during early preg
warfarin: can we reverse the effect?
- with vitamin K, effect within hours
- can give fresh frozen plasma (contains coag factors)
- prothrombin complex concentrate. (plasma-derived).
Parenteral direct thrombin inhibitors: what are they called?
2, both IV: argatroban, bivalirudin
parental direct thrombin inhibitors: mechanism?
bind and inactivate thrombin
argatroban: used for what?
treatment and prevention of thrombosis in HIT
bivalirudin and argatroban approved for what?
anticoag during percutaneous coronary interventiosn in patients with HIT
New Oral Anticoagulants: a few qualities?
very quick acting, no antidote, replacing warfain in many cases. NOT for renal insufficiency
Dabigatran: class? mechanism? clearance? side effects?
NOA. prodrug, converted in liver. directly inhibits thrombin.
cleared renally.
no monitoring, no antidote
side effects are bleeding and GI
dabigatran: approved for what?
stroke prevention in afib.
rivaroxaban: class? mechanism? clearance? side effects?
NAO. inhibits Xa directly. metabolized by liver.
renal clearance. no monitoring, no antidote
side effects: bleeding
rivaroxaban: approved for what?
prevention, treatment of acute VTE and stroke prevention in afib
fibrinolytic agents: what is their use?
break down thrombi.
fibrinolytic agents: mechanism?
converts plasminogen to plasmin, which degrades fibrin.
tissue plasminogen activator (TPA)
fibrinolytic agents: adverse effect?
bleeding
