5070: thromboembolism meds

what do antiplatelet medications do?

what don’t these do?

prevent platelet aggregation, suppress thrombosis

dissolve clots

what are anticlotting medications aka?

what do they do?

anticoagulants

interefere with the clotting cascade

what are thrombolytics?

drugs that lyse thrombi

aspirin is an irreversible inhibitor of what?

why can’t platelets not make new of this ?

COX-1

they don’t have a nucleus

during an acute MI, what dose of aspirin should be taken and what should they do to it?

325 mg of non-enteric coated aspirin

SHOULD BE CHEWED

if we suspect a stroke, what should we avoid?

and why?

aspirin

could be a hemorrhagic stroke, and worsen this

why do we give 325 mg of aspirin when you suspect an MI?

it is a loading dose large enough to inhibit platelets

the goal is to minimize the size of the clot that is still growing

what are the 5 adverse effects of clopidogrel?

bleeding, dyspepsia, abdominal pain, diarrhea, rash

what are 2 interactions with clopidogrel?

1. proton-pump inhibitors (like omeprazole) inhibit CYP2C19

2. cannabis also inhibits CYP2C19, primarily CBD

what genetic difference do people who are poor metabolizers of clopidogrel have?

how much benefit do they get from this drug?

allele of the gene for CYP2C19 that makes them poor metabolizers

gain little benefit from this drug

what medication is CI to take with erectile dysfunction medication?

nitroglycerin

what should the nurse wear while handling nitroglycerin paste?

gloves! or you will get a HA

what is included in the umbrella of manifestations of ACS? x3 things

unstable angina

NSTEMI

STEMI

what 2 therapies done during acute management of NSTEMI and unstable angina?

1. anti-ischemic therapy

2. anti-thrombotic therapy

why do we do anti-ischemic therapy during acute management of NSTEMI and unstable angina?

what is done during this ? x4 things

bc of narrowed vessels

1. O2 if pulse ox low

2. vasodilators (nitroglycerin)

3. B blocker (then calcium channel blocker if B blocker isn’t effective/CI)

4. PRN morphine sulfate/ACE inhibitors

   1. morphine not only reduces pain, but has venodilation effects

why do we conduct anti-thrombotic therapy in acute management of NSTEMI and unstable angina?

what 2 types of meds do we use for this?

preventing growth of clot and progression to STEMI or death

antiplatelet agents, anticoagulants

what conditions are antiplatelet/anticoagulants used to prevent or manage? x 5 things

1. DVT

2. atrial fibrillation sequelae

3. hypercoaguable states

4. supplement post-thrombolytic therapy

5. stent placement

what are thrombolytics used to treat which conditions? x 3 things

1. STEMI

2. ischemic stroke

3. pulm embolism

who will be given thrombolytics/antiplatelets/anticoagulants? x2 categories

1. people at risk for inappropriate clotting

2. people experiencing a medical emergency that need lysis of a clot

what is a general rule about medications for thromboembolic disorders?

they increase the risk of a bleed

combining 2+ meds from antiplatelet/anticoagulant categories increases the risk of what?

bleed

any drug that ____ the serum levels of the active form of antiplatelet/anticoag/thromboyltic med does what?

the opposite of this causes incr risk of what?

increases

increases risk of bleed

a clot

what does clopidogrel block?

what does this do?

P2Y12 receptor

blocks ADP stimulated activation of the gpIIb/IIIa receptor

if there is no COX-1 in platelets, what is not produced ?

thromboxane A2

at higher doses of aspirin, what is inhibited?

what does this inhibit down the line?

COX-2

prostacyclin

if we keep aspirin at a low dose, we _____ the inhibition of PGI2 while still inhibiting _____.

why is this useful?

minimize the inhibition

inhibiting TXA2

PGI2 inhibits platelets and vasodilates, counter-productive to inhbiit this

is clopidogrel a prodrug?

what is it primarily metabolized by?

yes

CYP2C19

genetic variations in CYP2C19 affects metabolism of which drug? what does it convert it to?

what does it cause generally ?

clopidogrel, its active form

variations in metabolism

if someone is a genetic “poor metabolizer” of clopidogrel, what does this mean?

they won’t get much effect from the drug

if a person is an ultra-rapid metabolizer of clopidogrel, what might they experience?

what do these include?

more adverse effects

bleeding

what is the result is the administration of clopidogrel and omeprazole?

omeprazole inhibits CYP2C19

this would cause poor metabolization of clopidogrel

anticoagulatns are ____ _____ medications

high alert

in pts over 65 years old, ______ are the most commonly implicated medication in ED visits

anticoagulants

what is the mech of warfarin?

what is the protein-bound status of this med?

anticoagulant, prevents active vit K regeneration

99% protein bound

what is the specific K dependent clotting factor that warfarin inhibits?

what does this do?

how does it do it?

VKORC1

prevents regeneration of the active form of Vit K

stopping the regeneration cycle at this point

what is the genetic component of the response to warfarin and what is affected?

variant alleles of the 2 genes that code

VKORC1 and CYP2C9

the presence of a variant in either or both of the genes that code for _____ and _____ can have a significant impact on the what?

CYP2C9 and VKORC1

the dose reduction needed to safely take warfarin

when taking warfarin, what should the patient have checked regularly?

what is the goal range of this?

INR

2-3

why should you tell your other providers, including dentist, if you are taking warfarin?

it helps them know that you are at risk of bleeding

what should a pt taking warfarin avoid? x 4 things

cuts/bruises/falls

other drugs that increase bleeding risk

what should patients taking warfarin maintain a consistent intake of what foods?

what should these patients wear?

foods containing vitamin K

medical alert bracelet

patients with cognitive dysfunction shouldn’t have free access to multiple tabs of what?

warfarin

what do heparin and enoxaparin increase the activity of ?

what does this inhibit? x 2 things

antithrombin

thrombin (factor IIa)

Factor Xa

how is enoxaparin different than heparin in its mechanism?

enoxaparin inactivates Factor Xa, has much less effect on thrombin

heparin inactivates both

what does antithrombin block? x 2 things

what does heparin bind directly to? x 2 things

thrombin and factor Xa

antithrombin and thrombin

what doesn’t heparin bind directly to?

factor Xa, but is in close proximity to it

what is the antidote to warfarin?

vitamin K

what is the antidote to heparin and enoxaparin?

what is the caviat to enoxaparin?

protamine sulfate

anti-factor Xa only partially neutralized

what should we monitor while the patient is taking heparin?

aPTT

what does HIT stand for?

what is this disorder caused by the formation of?

heparin-induced thrombocytopenia

antibodies to complexes of platelet factor 4 (PF4) and heparin

what is the process of HIT?

1. antibodies bind to the PF4-heparin complexes on quiescent platelet surface

2. induce platelet activation

3. incr release + surface expression of PF4

4. creates positive feedback loop

what is a devastating result of HIT? x 2 things

venous and arterial thromboses

what is the meaning of thrombocytopenia?

too little platelets in the body

once platelets are activated during HIT, what is released? and what does it cause?

what is the eventual end result of HIT?

procoagulant platelet microparticles

thrombosis and platelet consumption

thrombocytopenia

patients who’ve had a previous episode of ____ are at high risk for another episode.

what should be avoided in the future unless there is no alternative?

HIT

heparin

which version of heparin is much better at inactivating factor Xa than thrombin (IIa)?

enoxaparin (LMWH)

does factor Xa ever come into contact directly with the heparins?

no

is monitoring enoxaparin activity usually done with labs?

what is another test that could be ordered? who would this be for?

no

LMWH assay, esp for pts w low GFR

what is the MOA for dabigatran?

what does this prevent? x 2 things

directly inhibits thrombin

the conversion of fibrinogen to fibrin, prevents activation of factor XIII

dabigatran is a prodrug, where is it converted?

plasma and liver

what are the 2 ADE for dabigatran?

bleeding, gastritis-like complaints

what is the drug interaction for dabigatran?

what are 2 examples of this?

p-glycoprotein inhibitors

verapamil and carvedilol

what 2 conditions is dabigatran CI in ?

active bleeding

mechanical prosthetic heart valve

if a p-glycoprotein inhibitor is given with dabigatran, what is the resulting absorption and serum level?

increased

if a P-glycoprotein inducer is given with dabigatran, what is the resulting serum level?

decreased

what do p-glycoproteins do to drugs?

pump them out of cells and decreases their drug absorption

what is a pt teaching pt for dabigatran?x 2 things

why is this?

keep med in bottle with dessicant cap

don’t chew/crush this medication

it’s unstable when exposed to moisture

a patient came into the hospital vomiting blood, they were being given dabigatran capsules, but in what incorrect way?

opened capsules and sprinkling on patient’s food

what is the class of rivaroxaban?

what does it inhibit

anticoagulant,

factor Xa inhibitor

what 2 medications are CI if the patient is actively bleeding?

rivaroxaban, dabigatran

what is the reversal agent for rivaroxaban?

what does it do?

andexanet alfa

factor Xa decoy protein

binds to and inhibits rivaroxaban and apixaban

what does alteplase (tPA) activate?

what is the result of this?

plasminogen which activates plasmin

digested fibrin network of clots

what are thrombolytics also called?

what does alteplase (tPA) act like?

clot busters

endogenous plasminogen activators

what are the ADE’s of alteplase?

bleeding

what is CI against with alteplase? x 6 things

• prior hemorrhagic stroke,

• ischemic stroke w/in last 3 mo

• intracranial neoplasm

• serious head trauma

• internal bleeding

• aortic dissection

what kind of properties does fish oil have?

antiplatelet properties

statins are what type of inhibitors?

what do they do?

HMG-CoA-reductase inhibitors

1. inhibit cholesterol synthesis by inhibiting rate-limiting enzyme in cholesterol synthesis pathway

2. increases hepatic LDL receptors

3. reduced serum LDL

with regard to changing levels of cholesterol and triglycerides in the body, what do they do?

they also stabilize this….

decrease LDL

decrease triglycerides

increase HDL

atherosclerotic plaques

what are the 2 things that are essential to managing ASCVD risk ?

statins and healthy lifestyle interventions

what does the reduction of HMG-CoA reductase inhibition cause on the liver?

what does this permit the liver to do?

increased amounts of LDL receptors

take up more LDL from the plasma

what does ACL inhibitors stand for?

what do they do in the body?

and how?

adenosine triphosphate-citrate lyase

inhibit cholesterol synthesis

inhibiting another rate-limiting enzyme, which increases hepatic LDL receptors

what is the ultimate result of ACL inhibitors?

increased hepatic LDL receptors causes reduction in serum LDL

what is the MOA for dietary cholesterol blockers? x 2 things

prevent brush border cells of small intestine to inhibit dietary cholesterol absorption and reabsorption of cholesterol secreted in the bile

how does inhibited dietary cholesterol absorption (by dietary cholesterol blockers) affect intestinal cholesterol delivered to the liver?

what does this do to stored liver cholesterol?

plasma clearance of cholesterol?

decreases

decreases

increased

what is the effect of dietary cholesterol blockers on LDL and TG levels in the body? (LDL, TG, HDL)

decreased LDL

decreased TGs

small increase in HDL

what are fibrates MOA?

what are they primarily used to treat?

gene transcription mech w PPARa

elevated TGs

what actually is the PPARa family?

what do they do once activated? x 2 things

transcription factors

1. translocate to the cellular nucleus

2. regulate genes related to lipid an/or glucose homeostasis

what are omega-3 fatty acids used to treat primarily?

elevated TGs

what are the 2 classes of meds used to treat elevated tgs?

fibrates and omega-3 fatty acids

what are 3 ADEs of atorvastatin?

myalgias

myopathy

rhabdomyolysis

what are 4 interactions for atorvastatin?

1. fibrates, ezetimibe (inr risk of muscle injury)

2. red yeast rice supplements

3. CYP3A4 inhibitors (grapefruit juice)

what is the atorvastatin recommendation for pregnancy?

what about breastfeeding?

avoid in most pregnant women

not recommended

what is bempedoic acid meant to treat? x 2 things

familial hypercholesterolemia

established atherosclerotic CVD, as an adjunct to diet and statin therapy

what is the class of bempedoic acid?

adenosin triphosphate-citrate lyase (ACL) inhibitors

what are the thrombo/hyperlipidemia prodrugs? x 3 things

dabigatran, bempedoic acid, clopidogrel

what is the way that bempedoic acid is converted to a prodrug?

via liver glucuronidation (not CYP)

what are the ade’s of bempedoic acid? x 2 things

what is the interaction for this drug?

gout/hyperuricemia, tendon rupture

fluoroquinolone (incr risk for tendon rupture)

what class of drug is ezetimibe?

when is this indicated for?

in what two therapy methods could this be given?

dietary cholesterol absorption inhibitor

hypercholesterolemia

monotherapy or adjunct to statins

what is the MOA of ezetimibe?

how does it do this? x 2 ways

inhibition of dietary cholesterol absorption

1. at small intestine brush border

2. prevention of reabsorption of cholesterol secreted in bile

is the metabolite of ezetimibe active ?

yes