Oral Anticoagulant PK - grugirich Pharm D 5th year notes Fall PDF

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grugirich Pharm D 5th year notes Fall...

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Oral Anticoagulant PK WARFARIN o Basic Pharmacokinetics o S enantiomer is more potent  metabolized by different CYP enzyme than R enantiomer o Bioavailability: 95 – 100% o Onset of action: 0.5 – 4 hours o Peak: 1 – 6 hours o Vd: 0.1 – 0.2 L/kg o Protein Binding: 97-99% (primarily to albumin) o T 1⁄2: 40 hours (range: 36 – 42 hours) o Minimal renal clearance**  Pt w/ renal disease use warfarin instead of DOAC Renal Function and Bleeding: warfarin  Renal disease increases bleeding even if warfarin isn’t cleared renally o One compartment 

o Warfarin needs IV A.C + Warfarin o Pharmacodynamics o Warfarin doesn’t work on active clots (doesn’t inhibit synthesized clotting factory a  Prevents synthesis of new clotting factors II, VII, IX, X o 80% reduction of all clotting factors before you see a clinical anticoagulation effect o Clotting factors have ½ life  Factor VII: 2 – 6 hours (very short)  Synthesis is blocked right away  Factor IX: 18 – 40 hours  Factor X: 30 – 70 hours  Factor II (Thrombin): 72 – 120 hours  A week or more before clinically reduced thrombin  Times that it takes warfarin to be an A.C is when factor 2 is inhibited  Protein C: 8 hours  Vit K dependent CF is 2, 7, 8, 10

o Note the very long T 1⁄2 for Factors X and II. How long will it take to reach a new steady-state with warfarin?  7-9 days  CF 10 and 2 drive thrombosis more than Factor 7 and 9 o Theoretical concept: Are patients in a procoagulant state before an anticoagulant state?  YES, for the first few days  So… cover patient with LMWH for the first few days  It takes warfarin about 5 days to be an anticoagulant o Delayed onset of action for warfarin is due to the PD factors of these clotting factors o **Not testing on calculation of INR o Monitoring Warfarin: INR (International Normalized Ratio) bleeding time o Don’t measure serum warfarin concentrations o Measures the extrinsic coagulation pathway o Factors reflected in the assay:  INR measures: Factors I (fibrinogen), II (thrombin), V, VII, X  INR is a reflection of 7, 10, 2 as it relates to warfarin  7 shortest, 10, then 2 is longest o Prothrombin time isn’t standardized so we don’t monitor it o Derived from Prothrombin time (PT) ratio: time blood sample takes to coagulate o Why not just use the PT?  Variable from lab to lab o Normal INR you want is between 2-3.  Above 3 is increased risk of bleeding.  Less than 2, you aren’t anticoagulating the patient enough. o Do larger initial doses = faster time to therapeutic anticoagulation? o No, you have to look at the trend o Pt A and B both get 5 mg of warfarin. Do these two patients have similar intensities of anticoagulation? o No o **INR will increase when you give warfarin o Patient A: INR = 2.5, two days after starting warfarin  Factor 7 is reduced, but the 10 and 2 aren’t because it’s only been 2 days  So even though 2.5 is a higher INR, patient B is more overall reduced

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The INR jumped to 1.5 in two days, that’s something to be worried about. o Patient B: INR = 2.2, seven days after starting warfarin  Factor 7, 10 and 2 are reduced  More total reduction in coagulation factor  It doesn’t matter that he’s at 2.2, b/ it’s a steady increase. o Initiating Warfarin o NaiMve patient vs. previously treated o 5 mg vs. 10 mg initial doses (naïve pt) No difference in thrombin inhibition  Patients with 10 mg, got a far greater reduction in factor 7  Factor 7 is the first one to be affected o It’ll have a greater block, but it doesn’t mean pt is anticoagulated b/ you need all 4 to be blocked  36 hours-5 days o See no difference in patient in therapeutic range  They’ve gone past the goal o More risk of supratherapeutic /bleed  No clinically benefit using higher doses of warfarin b/ it didn’t get to goal faster, plus it overshot the goal  5 mg is still the initial dose b/ no clinical benefit of using 10 mg o How do you choose?  Previous warfarin dose vs. new to therapy?  Interacting drugs  Aspirin  clopidogrel  Comorbidities  Age  Where is the patient?  Hospital vs. Outpatient  Outpatient will be on a smaller dose  Need for anticoagulation  Acute event vs. preventive  What is the risk of adverse events?  How soon is follow-up visit?  How frequent is INR being obtained? o Warfarin Dosing o Lag between dose given & change in INR  Take warfarin dose at night and then wait 36 hours to get a lab 

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 Important to recognize at all times during therapy  The dose you give today won’t be shown tomorrow o Recognize the change in INR early (first 2 days) vs. later  Which clotting factors are the lab value sensitive to?  Which clotting factors do we care about clinically? o ***Drug Interactions o Increase INR will increase risk of bleeding o These drugs will increase risk of bleed (Basically any Ab has an interaction w/ warfarin)  normal flora will make vitamin K & so Ab will decrease normal flora  increase risk of bleed  Immediate effects: Require  dose right away (usually 50%)  Metronidazole (Flagyl)  Sulfamethoxazole/Trimethoprim (Bactrim)  Protease Inhibitors: Ritonavir, etc:  Macrolides: Erythromycin, Clarithromycin (NOT azithro):  Delayed effects:  dose within few days 

Amiodarone: wait 3 – 4 days, then  dose by 30-50%

o Dose dependent (more so Ld) o Amiodarone has large Vd  takes long time to reach SS  takes time for it to effect warfarin o Interaction: Amiodarone inhibits liver enzyme  increase warfarin effect  Azole Antifungals (some more potent than others, dose matters) o Large Vd  takes time to reach SS (5 days) o Azoles are CYP enzymes inhibitors which is how they effect the fungi, but they also effect human enzymes  Unknown/unpredictable effects:  Quinolones: monitor INR more frequently (dunno what to do) QOD or three times a week o Some patients have no interaction o Some have major interaction (INR > 8) o Some have effects immediately, some later o Directionality Matters o If pt already taking “interacting” drug  May not need to empirically  dose  Amiodarone warfarin o Follow INR closely, trend will identify warfarin dose

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o If patient taking warfarin 1st(expect an increase in INR)  Warfarin Bactrim  Reduce dose the day Bactrim is started b/bactrim works right away  Warfarin amiodarone  Wait a few days, than  dose because amiodarone won’t effect warfarin right away DOAC o Drugs o Direct thrombin inhibitor 

Dabigatran (Pradaxa) 

Falling out of BID w/ high risk of GI bleed o Falling out of favor

o Factor 10 inhibitors (XA) 

Apixaban (Eliquis)

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Edoxaban (Savaysa)

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Rivaroxaban (Xarelto)

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Betrixaban (Bevyxxa)

o Short ½ life vs warfarin long ½ life o Work right away vs warfarin (5 days to work) o Renally cleared vs warfarin isn’t o Monitor renal function o Monitor INR o Edoxaban: Start w/ IV A.C & then Edoxaban after 5 days o D, R, A only needs itself

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o Clinical Challenges w/ DOACS o DOACs are not routinely measured or monitored, unlike warfarin o In most patients, DOACs exhibit reliable drug exposure 

Are DOACs ok to use in patients with renal impairment? 

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ESRD: don’t use Dabigatran or Edoxaban o AUC increase as renal function declines  Increase in exposure o Dabigatran is most dependent on renal function o Apixaban PK (n=8)  Can use if crcl < 15 if patient has ESRD  If pt has ESRD exposure doesn’t change  We can still use apixaban o Warfarin and Apixaban can both be used in ESRD (< 15 ml/min Renal disease: you can use all but you must dose adjust o Apixaban cut dose by ½ (Age >80, wt < 60 kg, Scr >1.5)  Normal SCr (.9-1.3) o If patient has moderate renal impairment, apixaban is better than warfarin HD: Don’t need to decrease dose

o Rivaroxaban (n=8)  AUC will not change if patient is on hemodialysis  We can still use Rivaroxaban 

Are DOACs ok to use in patients with obesity? 

DOAC’s work in the plasma

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Obese pt have more plasma…so you think you’ll need a higher dose

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Evidence show not to increase dose, b/ they still have good anticoagulation effects

o Edoxaban and Renal Function (NAPLEX)  AF and ClCr> 95 ml/min don’t use o Guidelines: o If a patient is > 120 kg, don’t recommend DOAC, if you use do, check drug-specific peak and trough level o Overall exposure doesn’t change in rivaroxaban in pt > 120 kg o No open capsule of dabigatran o Opened increase AUC by 75%  increases exposure o Only 6% will be absorbed in the end… and that 6% is enough for it to be an A.C  Very poor bioavailability/ absorption  Has variable absorption Summary 

Warfarin o PK and PD must be taken into account clinically o “Loading” doses of warfarin not faster anticoagulation o Remember the lag time from dose given to clinical effect o Potential advantage in obesity – can measure INR for efficacy o Kinetics in ESRD/HD do NOT have better outcomes

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DOACs

o PK/PD different from warfarin, similar to each other • Less dosing variability o More dependent upon renal clearance, P-gp o Lots of unknowns!

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Drug concentration → safety, efficacy?

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How safe/effective are they in obesity?

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ESRD/HD – is renal clearance a significant barrier to use?...