2014B08 Outline the important pharmacological considerations when stopping warfarin and commencing
prophylactic (low dose) low molecular weight heparin in the peri-op period.

 

List:

·      Intro: aim, problems, risks

·      Bridging plans

·      PK

·      PD

 

Intro:

Aim

·   Minimize time with inadequate anticoagulation if at high risk (e.g mechanical mitral valve)

Problems

·   Warfarin: slow onset; long and variable duration of action

·   LMWH: short duration, parenteral only, only partially reversible

Risks

·   Of bleeding: Warfarin and LMWH have additive effects -> avoid overlap pre-op

·   Of clotting: Warfarin initially procoagulant -> ensure overlap post-op

 

Bridging plans:

Pre-op

·   Stop warfarin 5 x 24h pre-op

·   Start LMWH 1.5mg/kg daily 3/24 pre-op; 1mg/kg 24h pre-op then no more.

·   Check INR on AM of surgery; usually aim <1.5 (surgery dependent)

·   Warfarin reversal if required

o Vitamin K e.g. 2mg PO (6-12 hours), 5-10mg IV (12-24 hours)

o FF 2-4mL/kg + Prothrombinex 25-50 units/kg (immediate effect)

o FFP only 10-15mL/kg (immediate effect)

Post-op

·   Start LMWH 1.5mg/kg daily or 1mg/kg bd when safe

·   Start warfarin at same time

·   Cease LMWH when INR at target (e.g. 2-3)

 

Pharmacokinetics:

 

Warfarin

Low molecular weight heparins (LMWH)

Admin

·   PO daily

·   S/C therapeutic 1.5mg/kg daily or 1mg/kg bd

·   S/C prophylactic 40mg daily

Time course (normal)

·   Onset 8-12 hours

·   Peak anticoag 72 hours

·   Offset 3-5 days

·   Peak 4 hours

·   Offset 24 hours therapeutic dose 1.5mg/kg daily, 12 hours prophylactic (40mg in adult)

Absorption

·   Oral bioav 90%

·   Oral bioav minimal

Distribution

·   VD 0.1L/kg

·   Plasma protein binding >95% (albumin, own site)

·   Crosses placenta

·   VD 0.1L/kg

·   PPB >95% (AT3)

Metabolism

·   Phase 1 (multiple CYP) then Phase 2

·   t1/2β 40 hours

·   Minimal metabolism by heparinase (desulfation, depolymerization)

Excretion

·   Inactive metabolites -> urine and faeces

·   Mostly renal elimination

·   ↓GFR -> ↑duration hence ↓dose

Factors ↑duration

·   CYP inhibitor: e.g. cimetidine

·   Liver dysfunction: e.g. cirrhosis

·   Vit K deficiency: e.g. malnutrition

·   ↓GFR

 

Pharmacodynamics:

 

Warfarin

LMWH

Mechanism

·   Inhibit Vit K epoxide reductase

->↓ γ-glutamyl carboxylation

->↓ synthesis of zymogen

·   Pentasaccharide sequence binds and potentiates AT3 by conformational change

·   LMWH-bound AT3 inhibits coag factors

Anticoagulation

(and t1/2β)

Reduced synthesis of:

·   II (60), VII (6), IX (24), X (36)
(note long t1/2 II, X)

Inhibition of:

·   Xa:IIa (ratio 2-3:1)

·   Also VIIa-TF complex, IX, XI

Procoagulation

(and t1/2β)

Reduced synthesis of:

·   Protein C (8), protein S (30)
(note short t1/2 protein C)

·   Nil

 

 

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