2. PARENTERAL ANTI-COAGULANTS
HEPARIN:
-Biochemistry:
-glycosaminoglycan found in the secretory
granules of mast cells
-Heparan Sulfate:
-synthesized from the same disaccharide
precursor but undergoes less modification;
contains less sulfate groups but more
glucoronic acid and N-acetylglucosamine
3. PARENTERAL ANTI-COAGULANTS
HEPARIN:
-Source:
-commonly extracted from porcine intestinal mucosa or
bovine lung
-low-molecular-weight heparins are isolated from
standard heparin by:
a. gel filtration chromatography
b. precipitation with ethanol
c. Partial depolymerization with nitrous acid and
other chemical enzymatic reagents
*the biologic activity of low molecular weight
heparin is generally measured with a factor Xa
INHIBITION ASSAY, which is mediated by antithrombin
4. PARENTERAL ANTI-COAGULANTS
HEPARIN:
-Mechanism of Action:
-catalyzes the inhibition of several coagulation proteases by
antithrombin
-increases the rate of the thrombin-antithrombin reaction
by serving as a catalytic template to which the inhibitor and
protease bind
-induces conformational change in antithrombin that makes
the reactive site more accessible to the protease
-Heparin molecules containing less than 18 monosaccharide
units do not catalyze inhibition of thrombin
-antithrombin – inhibits activated coagulation factors of the
intrinsic and common pathways including thrombin, Xa and
IXa.; has little activity agains VIIa
5. PARENTERAL ANTI-COAGULANTS
HEPARIN:
-Pharmacological Effects:
-interfere with platelet aggregation and thus
prolongs bleeding time
-clears lipemic plasma in vivo by release of
lipoprotein lipase; may occur at concentrations
of heparin below those necessary to produce
anticoagulant effect
-lipoprotein lipase – hydrolyzes triglycerides to
glycerol and free fatty acids
6. PARENTERAL ANTI-COAGULANTS
HEPARIN:
-Clinical Use:
-initiate treatment of VENOUS THROMBOSIS and
PULMONARY EMBOLISM because of its rapid
onset of action
-started concurrently with an oral anticoagulant,
and is continued 4-5 days to allow oral
anticoagulant to achieve its full Rx effect
-Unstable Angina
-Myocardial Infarction
-DIC
7. PARENTERAL ANTI-COAGULANTS
HEPARIN:
-LMW HEPARIN vs STANDARD HEPARIN:
-LMW heparin has a more predictable pharmacokinetic
profile, which allows weight adjusted subcutaneous
administration WITHOUT laboratory monitoring
-LMW heparin have longer biological half-lives than do
standard preparations of the drug
-HEPARIN vs WARFARIN:
-In contrast to WARFARIN, HEPARIN DOES NOT cross
placenta and is not associated with fetal malformations,
HEPARIN IS DRUG OF CHOICE FOR ANTICOAGULATION
DURING PREGNANCY
-Heparin should be discontinued 24 hours before delivery to
minimize postpartum bleeding
8. PARENTERAL ANTI-COAGULANTS
HEPARIN:
-Absorption and Pharmacokinetics:
-NOT ABSORBED through GI mucosa and must be
GIVEN by CONTINUOUS IV infusion or SQ injection
-immediate onset of action thru IV; delay of 1-2 hours
SQ
-LMW heparin are absorbed more uniformly
DOSE ADMNISTERED IV PLASMA HALF-LIFE (t1/2) *Half-life is…
SHORTENED:
100 units/kg 1 hour -Pulmonary
Embolism
400 units/kg 2.5 hours
PROLONGED:
800 units/kg 5 hours -Hepatic cirrhosis
-ESRD
10. PARENTERAL ANTI-COAGULANTS
HEPARIN:
-Administration and Monitoring:
-Venous thromboembolism: bolus injection of 5000
units
-therapy is monitored routinely by aPTT, the target is
an elevation 1.8-2.5 times the normal value
-Initially, apTT should be measured and infusion rate
readjusted EVERY 6 HOURS, if steady dosage schedule
is established, daily monitoring is sufficient
-DVT prophylaxis – low dose therapy every 8 hours in
a hospital setting, NO NEED for LABS
12. PARENTERAL ANTI-COAGULANTS
HEPARIN:
-LMW Heparin Preparations:
-Enoxaparin, dalteparin, tinzaparin etcall
differ in composition and may have different
anti-factor Xa activity
-SQ weight adjusted regimen: 1-2 times daily
13. PARENTERAL ANTI-COAGULANTS
HEPARIN:
-Synthetic heparin derivatives:
-Fondaparinux (Arixtra) is a synthetic pentasaccharide based
on the structure of antithrombin binding region of heparin
-inhibits factor Xa by antithrombin but DOES NOT inhibit
thrombin d/t its short polymer length
-Administered SQ; reaches peak plasma level in 2 HOURS
-URINE t1/2: 17-21 hours NOT USED IN PATIENTS WITH
RENAL FAILURE
-given OD at fixed dose WITHOUT LAB MONITORING
-low incidence of thrombocytopenia
-indications: PE, DVT
-thromboprophylaxis: hip or knee surgery
14. PARENTERAL ANTI-COAGULANTS
HEPARIN:
-Toxicities:
1. Bleeding
-PRIMARY UNTOWARD EFFECT
-less with LMW heparin
-anticoagulant effect of heparin disappears
within HOURS after drug discontinuation
-effects of heparin can be antigonized by slow
IV infusion of PROTAMINE SULFATE (1mg PS / 100
units heparin up to 50mg over 10 minutes)
15. PARENTERAL ANTI-COAGULANTS
HEPARIN:
-Toxicities:
2. Heparin-induced Thrombocytopenia
-platelet count <150,000 uL or a 50% decrease from
pretreatment value
-occurs 5-10 days after Rx of standard heparin
-venous thromboembolism is MOST COMMON
-may be d/t the development of IgG antibodies against
complexes of platelet factor 4 leading to thrombin generation
-discontinued immediately if unexplained thrombocytopenia
occurs
-Dx confirmed through heparin-dependent platelet
activation assay
16. PARENTERAL ANTI-COAGULANTS
LEPIRUDIN:
-direct thrombin inhibitor
-excreted by the kidneys with a t1/2 of 1.3 hours
-used cautiously in patients with renal failure
-daily monitoring of aPTT
-no antidote
-alternative in patients with risk of developing
heparin-induced thrombocytopenia
17. PARENTERAL ANTI-COAGULANTS
BIVALIRUDIN:
-IV administration
-used as an alternative to heparin in patients going
coronary angioplasty
-t1/2: 25 minutes in patients with normal renal
function
-dosage must be reduced for patients with
moderate or severe renal impairment
18. PARENTERAL ANTI-COAGULANTS
ARGATROBAN:
-binds REVERSIBLY to the catalytic site of thrombin
-IV administration
-metabolized by hepatic CYPs and excreted in the
bile dosage reduction in hepatic insufficiency
- t1/2: 40-50 minutes
-alternative to lepirudin in patients with risk of
developing heparin-induced thrombocytopenia
19. PARENTERAL ANTI-COAGULANTS
DANAPAROID:
-mixture of nonheparin glycosaminoglycan
-heparan sulfate
-dermatan sulfate
-chondroitin sulfate
-used for prophylaxis of DVT
-mainly promotes the inhibition of factor Xa but DOES
NOT prolong the PT or a PTT
-prophylaxis: SQ with fixed dosage
-full anticoagulation: IV at a higher wt adjusted dose
20. PARENTERAL ANTI-COAGULANTS
DROTRECOGIN ALFA:
-recombinant form of human activated protein C
that inhibits coagulation by proteolytic inactivation
of factors Va and VIIIa
-has anti-inflammatory effects
-MAJOR ADVERSE EFFECT: BLEEDING
