Pharmacology Anticoagulants

Fondaparinau (arixtra) [Xa inhibitor] SE and PK?

SE: BLEEDING, irritation, bruising Contraindications: *-severe renal impairment* -Major bleeding *-Thrombocytopenia* -Bacterial endocarditis *Half life: 17 hours* 100% bioavailability -No evidence of metabolism

What drugs can be used in a patient needing anticoagulation BUT HAS HIT

Targeted Xa and IIa inhibitors: Fondaparinau (Xa) Hirudin, Bivalrudin (IIa) Argatroban, Melagatran (IIa)

*Heparin- warfarin Bridge PK?*

The anticoagulant effect peak effect is 1.5- to 3 days and duration is 2 to 6 days because of half life of clotting factors: Factor 7: 6 hours Factor 9: 24 hours Factor 10: 40 hours Factor 2: 60 hours Must keep the heparin therapy while you are waiting for warfarin to reach it's peak effect.

What is an important advantage of IIa inhibitors?

They do not cause HIT

How do anticoagulants work?

They prevent clot formation THEY DO NOT DISSOLVE CLOTS

What is Type I Non-Immune Thrombocytopenia?

Type I- BENIGN self limiting immune mediated disorder where platelets rarely go below 150 K/ (50 %) *Can use LMWH since they have 0.1 incidence of creating this type of thrombocytopenia vs regular heparins.* *No monitoring is required for LMWH!*

What is Type II IMMUNE TYPE Thrombocytopenia?

Type II- severe and life threatening disorder where platelets fall BELOW 100 K. *CANNOT USE HEPARINS→Use alternative anticoagulant therapy that are direct IIa (thrombin) inhibitors like Bivalrudin, Fondaparinux, lepirudin, argatroban Complication: *since warfarin monotherapy for HIT CAN CONTRIBUTE TO VENOUS LIMB GANGRENE* Hold warfarin until platelets recover above 100 K

What SE are associated with Dabigatran?

-17 % incidence of bleeding -DC drug since there is NO ANTIDOTE -Dyspepsia and GI complaints - take with food not antacids

Is monitoring required for Bivalrudin?

-ACT ( activated clotting time ) examination -Performed approximately 5 minutes after the bolus to confirm that the patient is fully anticoagulated (ACT goal 250-320 seconds) -It prolongs APTT and ACT

What DISadvantages are associated with Dabigatran?

-BID dosing -Short DOA -No antidote in case of OD -Bleeding risk -Severe SE of gastritis, reflux, -Dont chew tablet

Dabigatran (Pradaxa) PK?

-Breaks down in acidic environemnt, NO ANTACIDS -onset of action 1-2 hour peak -Dose adjustment required for ↓ RENAL FUNCTION -BID dosing because short half life *-NO MONITORING* *Unstable to moisture- used within 30 days* -Do not chew or break

Warfarin PK?

-Hydroxylated hepatically to an INACTIVE metabolite -Renal and Fecal Elimination *-CROSSES BBB → NOT GOOD IN PREGNANCY→FETAL HEMORRHAGE*

What are the DISadvantages of using Heparin?

-It is a heterogeneous mix of chains→PK is variable -HEPARIN INDUCED THROMBOCYTOPENIA= IMMUNE mediated

What advantage is associate with using Enoxyparin?

-Lab monitoring is not required -Long half life→ QD dose for prophylaxis and Q12h dose for DVT treatment -SC administration→at home administration -Lower incidence of non immune thrombocytopenia *If pt has IMMUNE thrombocytopenia then pt cant take HMWH or LMWH*

What advantages are associate with Dabigatran?

-More effective in reducing stroke and systemic embolism -NO MONITORING INR -Few drug and food interactions

What interactions are associated with Dabigatran?

-Not metabolized therefore there are no cytochrome DI's -P-glycoprotein Interactions: Inducers of the transporter: St John's Wort, tenofovir Inhibitors of the transporter: amiodarone, verapamil, clarithromycin

What are the advantages of using Heparin?

-Rapid Onset -Can be used prophylactically→routine monitoring of aPTT in prophylaxis is NOT necessary *-Excellent dose control.* Must stop when there is heparin induced thrombocytopenia

Low molecular Weight Heparins [Enoxyparin (Lovenox)] MOA?

-Same as Heparin -*endogenous release of tissue factor(extrinsic (pathway inhibitor)*→ may affect leukocyte procoagulation enzymes and thrombogenesis *-HAS A HIGHER IIA AND XA ACTIVITY*

How to switch from Warfarin to Dabigatran?

-Stop warfarin , start dabigatran when INR is less than 2 Switch from dabigatran to warfarin is based on renal function (CrCl)

Fondaparinau (arixtra) [Xa inhibitor] MOA?

-Synthetic SUBCUTANEOUS drug -Inhibits activity of ONLY factor Xa INDIRECTLY through antithrombin III(ATIII). -Fondaparinau binds to antithrombin III→ induces a conformational change in antithrombin that has increased affinity for factor Xa→inhibitory effect of antithrombin against Xa→inhibits thrombin formation *requires NO MONITORING and bleeding risk is small*

How does Heparin cause intervention on the clotting cascade?

It has a wide attack on the intrinsic clotting pathway.

What DISadvantage is associated with using [Enoxyparin (Lovenox)] ?

Long acting→ CANT SHUT OFF IT'S EFFECTS RAPIDLY→NOT GOOD when you have bleeding side effect! -

High Molecular Weight (unfractionated) Heparin MOA and PK?

MOA: -Accelerates formation of antithrombin-III-thrombin complex (our natural anticoagulant) →*Inactivates IIa [thrombin], IXa and Xa* -Prevents fibrinogen → fibrin PK: -IMMEDIATE ONSET -CONTINUOUS IV drip -DOESN'T CROSS PLACENTA so it is okay to use in pregnancy -Slight liver metabolism

Heparin monitoring and drug interactions?

Monitoring Parameter: Activated partial thromboplastin time (APTT) *Drug interactions with these ANTAGONIZE anticoagulation→cause clotting:* -ANTIHISTAMINES -CARDIAC GLYCOSIDES (drugs for CHF) -Nicotine -Tetracyclines *Drug interactions with these INCREASE anticoagulation→cause bleeding:* -Platelet inhibitors (Plavix, aspirin) -Oral anticoagulants -IIb/IIIa inhibitors (Reopro)

Rivaroxaban (Xarelto) [Xa inhibitor]

New ORAL Xa inhibitor *Caution: bleeding risk with liver disease* Drug Interaction with 3A4 inhibitors and inducers. P-glycoprotein inhibitors -overdose -NO ANTIDOTE

Apixaban (Eliquis)

New ORAL Xa inhibitor Approved for stroke and atrial fibrillation Caution: bleed and ↑ stroke with discontinuation Drug Interaction with 3A4 inhibitors and inducers. P-glycoprotein inhibitors -overdose -NO ANTIDOTE

In which cases is Bivalrudin used?

Percutaneous coronary intervention Acute coronary syndrome Intervention in patients with HIT

Heparin-induced Thrombocytopenia is defined as...

reduction of platelets to 50 % (150K/microliter) within 5-10 days of heparin use -An adverse, *immune- mediated* reaction to Heparin, forming antibodies to the heparin-platelet factor 4 (ca++)complex Findings: -Bruises, petechia, purpura, plaque, necrosis, increased BP, tachyarrythmias

What anticoagulants are used?

*1. High molecular weight Heparin *(unfractionated) - *continuous IV drip* *2. Low molecular weight Heparin:* -enoxyparin (Lovenox) (fractionated) - *q 12h subceutaneous* *3. Anticoagulation for patients with heparin-induced thrombocytopenia (HIT):* a. fondaparineau (Arixtra) - Xa b. bivalrudin (Angiomax)-IIa *4. Oral Anticoagulants* a. Warfarin (Coumadin) b. Dabigatran (Pradaxa)

Targeted IIa (Thrombin) Inhibitors:

*Bind at 2 sites:* Bivalrudin (Angiomax) IV *Bind at 1 site:* Dabigatran (Pradaxa) PO Argatroban

Heparin SE?

*HEMORRHAGE: * 1. with excessive dose 2. extended APT time 3. Thrombocytopenia (blues) -Hypersensitivity reaction -Hyperkalemia via aldosterone suppression -Alopecia and osteoporosis

[Enoxyparin (Lovenox)] SE and PK?

*hemorrhage, thrombocytopenia, hypochromic anemia, ecchymoses (subdermal hemorrhage) bleeding complications* -CNS confusion PK: -2-3 hour onset post SC injection -Unknown metabolism -Half life= 4.5 hours -Distribution= 6L into blood -CAN BE USED in renal dysfunction but must be AJUSTED

Protamine sulfate MOA?

*neutralizes heparins anticoagulant effects of high molecular weight heparins BUT NOT LMWH* -Stop Heparin administration in a minor bleed -Stop Heparin and give Protamine if it is a MAJOR bleed. Give 1 mg Protamine/100U of the last dose of heparin . Administer slowly to avoid histamine release and vascular shock.

Bivalrudin (Angiomax) MOA?

A synthetic 20 aminoacid peptide IV Drug MOA: Binding the catalytic AND anion-binding site of *circulating and clot-bound thrombin* → Ultimately inhibiting fibrin and factor XIII formation *Reduce dose with renal function*

Warfarin Drug Interactions?

Any interaction that can cause overdosing→Hemorrhagic death or thromboembolic death ↑ Effects (Bleeding) seen with: Vitamin E, Heparin, aspirin, NSAIDs, antibiotics, glucagon, cimetidine, thyroid hormone ↓Effects (thrombosis) seen with: Barbiturates, corticostreoids, penicillins, contraceptives, cholestyramine, rifampin

What are the benefits of using Bivalrudin vs Heparin?

Bivalrudin: -has 100% bioavailability -DOES NOT REQUIRE ANTITHROMBIN AS A BINDING COFACTOR -Does not activate platelets -Has a 25 min half life so has fast "on-off" capability

Dabigatran (Pradaxa) MOA?

Direct ORAL thrombin (IIa) inhibitor PRODRUG MOA: Direct thrombin (IIa) competitive inhibitor→alters conversion of fibrinogen to fibrin inhibits thrombin induced platelet aggregation

Xa Inhibitors:

Fondaparinau (arixtra) Rivaroxaban (Xarelto) Apixaban (Eliquis)

Warfarin SE?

GI: NVD, anorexia, cramps, mouth ulcerations, sore mouth Prolonged PT, INR [OPTIMUM=2-3], APTT, anemia hemorrhage (with excessive dosage) Hepatitis, elevated enzymes, ↓function, jaundice

How does Fondaparinau compare to LMWH in terms of HIT, platelets and half life?

HIT: Does not occur with Fondaparinau Platelets: Fondaparinau does not affect function or aggregation while LMWH has some effect Biovailability: Both 100% Half life: Fondaparinau (15-18 hours so WD dosing). LMWH (4 hours so BID dosing).

Warfarin antagonist Phytonadione

Promotes clotting factors 2,7,9,10 Aqua-mephyton - 10 mg INJECTION (bleed) Mephyton - 5-10 mg PO (no bleed)

What drug is used to back titrate an overdose of Heparin?

Heparin Antagonist *Protamine sulfate *

Warfarin (Coumadin) MOA:

In a dose dependent manner inhibits vitamin K reductase and vitamin K epoxide reductase → INHIBITING VIT K FUNCTION→inhibits hepatic synthesis of clotting factors that are stimulated by Vitamin K: *2,7,9,10 * It also inhibits endogenous anticoagulant protein C and S

Oral Anticoagulants...

Warfarin (Coumadin)-monitoring required Dabigatran (Pradaxa)-no monitoring required/no antidote

Warfarin (Coumadin) PK:

Warfarin: Rapid, complete GI Absorption 99.3 PB 36 hours onset Bishydroxy Coumarin: Slow, incomplete GI absorption 99% PB +48 hours onset The peak is reached 60-120 hours→ explains why you must bridge Heparin-Warfarin

Bivalrudin SE?

back pain, pain, nausea, headache, and *hypotension* *An unexplained fall in blood pressure or hematocrit→ serious consideration of a hemorrhagic event and cessation of administration*