CHEST 2012-Parenteral Anticoagulants Flashcards
Heparin MOA
Heparin binds to positively charged residues on Antithrombin (AT) and causes conformational change of AT’s arginine reactive center.
Conformational change converts AT so that it quickly binds covalently to the active center serine of Thrombin and other coag factors (aka allows AT to become a fast inhibitor of serine proteases).
AT’s covalent bond to the coag enzymes irreversibly inhibits their procoag activity.
Heparin then dissociates from AT and is reused.
Heparin molecule size
Heparin molecules range in molecular weight from 3,000 to 30,000 kDa with a mean of 15,000, which corresponds to approximately 45 saccharide units
The fraction of heparin molecules that contain the high-affinity pentasaccharide sequence needed for anticoagulant activity
Only about one-third at therapeutic concentrations
Clearance of heparin’s high-weight vs low-weight molecules
High-weight moieties are more rapidly cleared vs low-weight
Binding of heparin to AT catalyzes the inactivation of which factors at therapeutic concentrations?
Thrombin, IIa, Xa, IXa, XIa, XIIa, VIIa
Antithrombin targets proteases on the contact activation pathway (intrinsic pathway): activated forms of Factor X (Xa), Factor IX (IXa), Factor XI (XIa), Factor XII (XIIa), Factor II (thrombin) (IIa).Also Factor VII (VIIa) from the tissue factor pathway (extrinsic pathway).
If Thrombin is reduced b/c of heparin, what other effects on the coag cascade will result?
Decrease in fibrin formation, thrombin-induced platelet activation, and decreased V, VIII, and XI formation
How does heparin cause osteoporosis?
Heparin inhibits osteoblast formation and activates osteoclasts, which promotes bone loss
Heparin route of admin
Heparin is not absorbed orally and therefore must be administered parenterally.
The two preferred routes of administration are by continuous IV infusion or subcutaneous injection.
If an immediate anticoagulant effect is required, a higher initial subcutaneous dose of heparin can be administered. Alternatively, an IV bolus of heparin can be given in conjunction with the first subcutaneous dose.
Heparin dosing suggestion for SQ vs IV
SQ dose of heparin should be higher than the usual IV dose because subcutaneous administration is associated with reduced bioavailability.
Heparin dosing suggestion if immediate anticoag effect is needed
A higher initial SQ dose, or an IV bolus of heparin can be given in conjunction with the first subcutaneous dose.
Initial dose of heparin for VTE
Either weight-based (80 units/kg bolus and 18 units/kg/h infusion) or administered as a bolus of 5,000 units followed by an infusion of at least 32,000 units/day.
If heparin is given subcutaneously for treatment of VTE, there are at least two options: (1) an initial IV bolus of ∼5,000 units followed by 250 units/kg twice daily; or (2) an initial subcutaneous dose of 333 units/kg followed by 250 units/kg twice daily thereafter.
Heparin dose for ACS (Unstable Angina, NSTEMI, STEMI)
The doses of heparin recommended for treatment
of acute coronary syndromes are lower than those
used to treat VTE.
Heparin bolus of 60 units/kg (max 4,000 units) then infusion of 12 units/kg/h (max 1,000 units/h)
Tests to monitor heparin doses
When given in therapeutic doses, the anticoagulant
effect of heparin is usually monitored using the aPTT. (goal is 1.5-2.5 times the normal)
Activated clotting time (ACT) is used to monitor the
higher heparin doses given to patients undergoing
percutaneous coronary interventions or cardiopulmonary bypass surgery.
Reversal agent for heparin, and dose
Protamine sulfate
1mg binds to 100 units of heparin
Calculate protamine dose based on amount of heparin given over the last 2-3 hours (b/c heparin’s half-life is 60-90 mins if given IV)
Possible side effects of Protamine sulfate
Hypotension or bradycardia–can be minimized by administering the protamine slowly.
If previously received protamine sulfate-containing insulin, undergone vasectomy, or have known sensitivity to fish–increased risk to have preformed antibodies against protamine sulfate and to suffer from allergic reactions, including anaphylaxis. Pretreat with corticosteroids and antihistamines.
Why LMWH inhibit Xa more than Thrombin
Most molecules are too short to allow bridge to form between LMWH-AT complex and Thrombin. LMWH inactive Xa more b/c the LMWH-AT complex does not need this bridge to perform its inactivation reaction.
Half-life of LMWH
3-6 hours after SQ injection, but can be prolonged in renal failure
Time of peak anti-Xa level after SQ dose of LMWH
3-5 hours
Goal anti-Xa level for LMWH for VTE treatment
0.6-1 unit/mL, measured 4 hours after dosing. May be higher than 1 unit/mL for once daily dosing regimens
Dosing adjustment considerations for LMWH in obese patients
Increase dose (use actual body weight)
Enox–adjust up to 144kg
Tinzaparin–up to 165kg
Dalteparin–up to 190kg
Reversal agent for LMWH, and dose
Protamine sulfate
Give only if LMWH dose was within last 8 hours
1mg per 100 anti-Xa units of LMWH
(note 1mg Enox=100 anti-Xa units)
Max single PS dose of 50mg
Ok to give second dose of 0.5mg/100 anti-Xa units if still bleeding
Fondaparinux MOA
Binds to AT and produces a conformational change at the reactive site of AT that enhances its reactivity with factor Xa.
AT then forms a covalent complex with factor Xa. Fondaparinux is released from AT and is available to activate additional AT molecules.
Because it is too short to bridge AT to thrombin, fondaparinux does not increase the rate of thrombin inhibition by AT.
Fondaparinux half-life
17-21 hours
Reason for fondaparinux contraindicated in CrCl < 30 mL/min
Drug is almost completely dependent on renal clearance
Fondaparinux dose for VTE prophylaxis and ACS
2.5mg once daily SQ
Fondaparinux dose for VTE treatment
Weight-based dose
<50kg = 5mg SQ daily 50-100kg = 7.5mg SQ daily >100kg = 10mg SQ daily
Fondaparinux dosing requirement if moderate renal impairment (CrCl 30-50mL/min)
Decrease dose by 50% or switch to low-dose heparin
Does protamine sulfate work for bleeding with fondaparinux?
No
Protamine sulfate does not bind to this drug
Reversal agent for bleeding with fondaparinux
Recombinant factor VIIa
MOA of direct thrombin inhibitors
Bind to thrombin and block its enzymatic activity and effects on fibrin formation, platelet aggregation, and the coag cascade
Bivalirudin use
Alternative to heparin when undergoing PCI or in patients with HIT
Bivalirudin dose
0.75mg mg/kg bolus, then 1.75mg/kg/hr infusion
Half-life of Bivalirudin
25 min after IV injection
Argatroban half-life
45 minutes
Argatroban metabolism
Liver via CYP 3A4/5 enzymes, so caution in liver inpairment
Not renally excreted, so useful in patients with HIT and severe renal function
Argatroban dose
2mcg/kg/min infusion
Adjust to maintain aPTT in 1.5-2.5 range
Reversing bleeding with DTI’s
No specific antidote, but recombinant factor VIIa may theoretically be useful to generate thrombin.
Hemodialysis can remove bivalirudin or argatroban
