2017A08 Compare and contrast low molecular weight heparin and unfractionated heparin.

 

List:

·      PC

·      PK

·      PD

 

Physicochemical:

 

Unfractionated heparin (UFH)

Low molecular weight heparin (LMWH)

MW

5-25kDa

~4.5kDa

Derivation

Pig intestine

Cow lung

Same

Aqueous solution

Y

Y

 

Pharmacokinetic:

 

UFH

LMWH

Admin

·   S/C bd prophylaxis

·   IV infusion therapeutic

·   S/C prophylaxis daily

·   S/C therapeutic 1mg/kg bd or 1.5mg/kg daily
(more convenient)

Time course

·   Onset IV <5 min

·   Onset S/C 2 hours

·   Offset therapeutic IV infusion: 6 hours

·   Peak: 2-4 hours

·   Offset prophylactic: 12 hours

·   Offset therapeutic: 24 hours

(↑ if renal impairment)

Absorption

·   Good subcut bioav

·   Good subcut bioav

Distribution

·   VD 0.1L/kg

·   Plasma protein binding >95%

o 1/3 AT3

o 2/3 other (albumin etc.)

·   Doesn’t cross placenta as much

·   VD 0.1L/kg

·   Plasma protein binding >95% (almost all AT3)

·   Does cross placenta

Metabolism / excretion

·   Variable rate

·   Zero order kinetics at high doses.

·   Heparinase: desulfation, depolymerisation

·   Small amount urine unchanged

·   t1/2β 90 mins

·   Less variable rate

·   ?First order

·   Some by heparinase

·   Most in urine unchanged

·   t1/2β ~5 hours

·   ↓Dose in renal impairment

 

Pharmacodynamic:

 

UFH

LMWH

Therapeutic:

 

 

MoA

·   Binds AT3 -> change shape
(30% of heparins have a pentasaccharide sequence that binds AT3)

·   Same

Factors inhibited

·   II:X ratio = 1:1 (Only saccharides >18 long can bridge AT3 and II)

·   Also 11, 9, VIIa:TF complex

·   IIa:Xa ratio = 1: 2-3

Platelet activation

·   Yes

·   Minimal

Reversibility with protamine

·   Near 100%

·   Risk rebound anticoag as t1/2β longer than protamines (90 cf. 60)

·   ~60%

·   Note risk re-bound anticoag as more is absorbed from S/C fat

Monitoring

·   aPTT (titrate to 1.5-2.5x control)

·   Mandatory if infusion (↑variable response due to many binding sites)

·   FXa (less available)

·   Usually not needed (bound to AT3 only, less variable)

Side effects:

 

 

Heparin-induced thrombocytopaenia

·   1/200 therapeutic dose

·   1/1000 prophylactic dose

·   ↓Risk

Bleeding

·   ↑Risk (1-5%)

·   But can reverse

·   ↓Risk

·   But can’t fully reverse

Other side effects

·   Deranged LFTs

·   Osteoporosis

·   Skin necrosis

·   Alopecia

·   IV bolus: hypotension

·   Similar to UFH but lower risk

 

 

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