Specifics of Anticogulant Drug Classes: Parenteral Anticoagulants and Oral Anticoagulants (Bessada)

what is a side effect of ALL anticoagulants

bleeding

what are the 2 types of parenteral anticoagulants used mostly

unfractionated heparin (UFH) abdominal LMWH/ Enoxaparin

MOA of unfractionated heparin

binds to ad activates antithrombin, which in turn inactivates factor Xa and thrombin (factor lla)

descrive UFH VTE dosing

IV infusion ONLY--> weight-based dosing & adjusted via nomogram

what is a key counseling point about UFH?

can be porcine-derived so ask patients if they don't consume pork

describe UFH therapeutic monitoring

close monitoring required (unpredictable patient response) either via aPTT or mostly anti-Xa level

describe anti-Xa UFH therapeutic monitoring

provides heparin concentration using a calibration curve

-tends to be more accurate in hospitalized, acute medically ill patients

-should NOT be used after LMWH or DOAC

when should u measure anti-Xa levels for UFH monitoring

-prior to initiation/baseline

-evaluate response 6 hours after initiation or dose change

what is "heparin resistance"

some patients will have a diminished response to UFH

-suspected in patients who require > 40,000 U of UFH/24 hour period

-adjust dose based on anti-Xa concentrations

what are the 2 ADEs with UFH

thrombocytopenia (platelets

describe heparin induced thrombocytopenia (HIT)

should be suspected when 30-50% drop in platelet count but remain above 150,000

what is the diagnostic screening for heparin induced thrombocytopenia

4T's

-thrombocytopenia

-timing of platelet count fall (5-10 days after)

-thrombosis

-or oTher explanation for falling platelets

what are thr diagnostic labs for heparin induced thrombocytopenia

PF4, SRA

describe the treatment of heparin induced thrombocytopenia

-stop heparin products

-direct thrombin inhibitors

compare IV vs SQ UFH

IV only for VTE treatment

VTE prophylaxsis= SQ

is LMWH or UFH preferred in VTE treatment? what are the 2 exceptions of this

LMWH> UFH

unless

-poor kindey function (not renally cleared)

-has upcoming surgeries/procedures (fast off)

MOA of LMWH

shorter chain primarily targets factor Xa, less factor lla inhibition vs UFH

what are the 3 LMWHs

enoxaparin

dalteparin

tinzaparin

enoxaparin dose (VTE treatment)

1mg/kg BID SQ

describe LMWH therapeutic monitoring

monitoring is not necessary d/t predictable anticoagulant response with SQ administration

get baseline labs (CBC with platelets + SCr)

ADEs of LMWH

-bleeding (less than UFH)

-epidural & spinal hematomas possible if pts have epidural catheter

-thrombocytopenia, avoid with HIT hx/diagnosis

is LMWH safe in pregnancy?

yes, it doesn't cross the placenta

why is LMWH 1st line for VTE treatment

-predictable anticoagulation dose response

-lower incidence of thrombocytopenia

-reduced need for lab monitoring

-improved SC bioavailability

-dose-dependent clearance

-longer half-life

when are the 2 situations when UFH is preferred over LMWH

- poor kidney function (not renally cleared)

-upcoming procedures (IV can be easily turned off, faster half-life)

MOA of fondaparinux

selectively inhibits factor Xa activity

-no direct effect on thrombin (lla) activity

-no effect on platelet function

describe the clearance of fondaparinux and enoxaparin

both cleared renally

describe fondaparinux

-SQ

-long elimination half-life

-no specific antidote

-no routine coagulation testing required

when is fondaparinux generally used

in the setting of HIT (because no effect on platelets) in treatment or prophylaxis

what are the names of the 2 IV direct thrombin inhibitors

argatroban and bivalirudin

MOA of direct thrombin inhibitors

direct inhibition of factor ll (thrombin) activity

-not via antithrombin

-no effect on platelet functiion

describe the contraindications with direct thrombin inhibitors

-argatroban is hepatically cleared (don't use/monitor with poor liver function)

-bivalirudin is renally cleared (don't use/monitor with poor kidney function)

describe IV direct thrombin inhibitor VTE dosing

weight-based dosing & adjusted via nomogram (like UFH)

when are direct thrombin inhibitors (argatroban & bivalirudin) used

VTE treatment only in the setting of HIT

what are the 2 reasons why warfarin requires continuous monitoring and patient education

-narrow therapeutic index

-many food and drug interactions

warfarin MOA

inhibits the SNOT clotting factors and the body's natural anticoagulants (protein C and S)

how long until we see warfarin's full effect? why?

42-72 hours

this is how long it takes to inhibit all SNOT Factors (II takes 42-72 hours)

when is most thrombotic periiod (highest risk of clot) in warfarin initiation? why?

first 30 hours

not fully treated + natural anticoagulants are being inhibited (protein S inhibited in 30 hours)

describe the potency of the 2 warfarin isomers

the S isomer is 2-4 times more potent than the R isomer

describe warfarin metabolism

S isomer: CYP2C9

R isomer: CYP3A4

describe warfarin monitoring via PT

was historically used but every lab uses different reagents and machines so PT can vary

what is protothrombin time (PT)

represents the time (in secs) required for plasma to form a clot in the presence of Ca and tissue thromboplastin, which activates extrisic pathway

describe warfarin monitoring via INR

standardized across all labs (unlike PT)

target= 2.5 (2-3)

describe the frequency of outpatient INR monitoring for warfarin

-initially twice the first week

-once dose established, q 1-2 weeks until INR stabilizeed

-then check q 4-6 weeks (or q12 weeks in stable patients)

-recheck 1 week from a dosage change, then q1-2 until stabilized, then q4-6

describe the frequency of hospitalized INR monitoring for warfarin

most US systems check daily until the INR is in the therapeutic range for 2 consecutive days (not efficient because won't see a change in INR for a few days anyways)

why is the INR range for warfarin 2-3?

describe warfarin dosing

individualized based on desired target INR range & patient response

usually started on 5mg/day

what are 6 factors that warrant a lower starting dose of warfarin?

- 65+ y/o

-elevated baseline INR

-poor nutritional status

-liver disease

-genetic polymorphisms

-concurrent interacting meds (2C9, 3A4)

describe the PK that causes warfarin to have DDIs

Drugs inhibiting/inducing CYP 2C9, 1A2, 3A4 isoenzymes have the greatest potential to impact INR/bleeding

describe the PD that causes warfarin to have DDIs/FDIs

-concomitant blood thinners: Aspirin, P2Y12i

-Foods with varying amounts of vitamin K can increase/decrease INR and bleed/thrombosis risk → patient must be consistent with diet

which 3 drugs increase INR/anticoagulation with warfarin

amiodarone

fluconazole

sulfamethoxazole

(3A4, 2C9 inhibitors)

which 4 factors decrease anticoagulation/INR with warfarin

carbamazepine

phenytoin

rifampin

vitamin K

(3A4, 2C9 inducers)

what 3 drugs increase the bleed risk with warfarin?

aspirin

NSAIDs

blood thinners

ADEs of warfarin

-doesn't cause but exacerbates bleedin (GI, intracranial hemorrhage)

-warfarin-induced skin necrosis

-purple-toe syndrome

when are warfarin ADEs most likely to occur?

new initiation, first 24-42 hours

when should warfarin be taken

in the evening

describe patient education of warfarin

-importance and need for INR follow-up

-keep diet consistent (vitamin K foods)

-inform any HCP that they're on warfarin

-talk with pharmacist and physician before any med changes

-watch for bleeding

-be cautious of falls/hits on the head

how to treat pain if on warfarin

APAP! (avoid NSAIDs/aspirin because they increase your bleed risk)

are DOACs or VKA's preferred for VTE

DOACs

describe DOAC monitoring

don't require INR monitoring but require q3-6 months:

-kidney and liver function

-CBC

body weight

-DDIs

describe the metabolism of rivaroxaban and apixaban

CYP3A4 and P-gp substrates

describe the metabolism of edoxaban and dabigatran

P-gp substrates

P-gp/3A4 inhibitors? effect?

increase bleed risk by increasing the concentrations of DOACs

amiodarone

propafenone

quinidine

verapamil

P-gp/3A4 inducers? effect?

increase clot risk by increasing the concentrations of DOACs

carbamazepine

rifampin

what are the 4 times when DOAC should be used?

-1st line therapy for acute VTE

-normal renal and hepatic function

-less frequent monitoring

-insurance coverage

what are the 3 times when DOAC should be used with caution?

-poor kidney function

-poor liver function

-under/overweight

what are the 5 times when DOAC should not be used?

-strong CYP3A4 inhibitors/inducers

-mechanical heart valve

-rheumatic heart disease

-pregnancy

-triple-posiitbe antiphospholipid syndrome