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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