DRUG TRENDS
SA JOURNAL OF DIABETES & VASCULAR DISEASE
42
VOLUME 7 NUMBER 1 • MARCH 2010
Drug Trends
Managing warfarin use in diabetic patients
W
arfarin, the only available oral cou-
marin anticoagulant in South Africa,
is widely prescribed for the prevention
and management of arterial and venous
thrombo-embolism. It has a narrow thera-
peutic index and a wide inter-individual
variability in its therapeutic response.
Importantly, the target therapeutic
range of the international normalised ratio
(INR), the key measure of warfarin antico-
agulation that is required to prevent venous
thrombo-embolism in diabetic and other
high-risk patients is 2 to 3, whereas for
double valve replacement, it is somewhat
higher at 2.5 to 3.5. However, factors such
as age, gender, body mass index, inter-
acting drugs and genetic polymorphisms
(VKORCI and CYP2C9 genes) influence the
dosage needed to maintain the INR in the
target therapeutic range.
1
Generally, if the INR falls below 2, this
is associated with an increase in throm-
botic events, and an INR above 4 with an
increased risk of haemorrhagic events.
However, wide inter-individual variability
in therapeutic response does pose major
challenges to the clinician. While newer
oral anti-coagulants such as dabigatran
are showing great promise, it is likely that
many patients in South Africa will still
require and be treated with warfarin.
A brief review of the pharmacology of
warfarin and drug interactions with warfa-
rin, particularly those drugs used within a
diabetes environment, is useful for achiev-
ing a reliable anticoagulation status.
Pharmacology of warfarin
Commercial warfarin is a racemic mix-
ture of the S and R enantiomers. Follow-
ing ingestion, it is completely absorbed,
with 99% being bound to albumin in the
plasma. The unbound fraction undergoes
biotransformation in the liver by the cyto-
chrome P450 system (CYP).
S-warfarin is a five-times more potent
vitamin K antagonist than R-warfarin.
S-warfarin is metabolised by CYP2CP
into inactive metabolites and eventually
excreted in the bile. The R-enantiomer is
metabolised by CYP1A1, CYP1A2 and
CYP3A4 into inactive alcohols that are
then excreted in the urine.
2
The molecular target for warfarin is the
vitamin K epoxide reductase (VKOR). VKOR
reduces vitamin K epoxide to vitamin K,
which is essential for the carboxylation of
vitamin K-dependent clotting factors II,
VII, IX and X and proteins Z, C and S. The
anticoagulant effect of warfarin is exerted
by its ability to disrupt gamma-glutamyl
carboxylation of the vitamin K-dependent
clotting factors and therefore the clotting
cascade.
Although VKOR has been known for
decades, the gene that encodes for it, vita-
min K epoxide reductase complex subunit
1 (VKORC1) was only discovered in 2004.
Since its discovery, there has been a great
deal of research investigating the influence
of VKORC1 mutations on warfarin dose
requirements.
Warfarin resistance
Warfarin resistance is defined as warfarin
dose requirements greater than 70 mg/
week to maintain INR in the target thera-
peutic range. The resistance may be inher-
ited or acquired, but the prevalence of true
warfarin resistance is rare. The proposed
mechanisms of resistance involve various
pharmacokinetic and pharmacodynamic
factors.
Interactions with warfarin
Broad classes of drugs and some specific
drugs as well as over-the-counter agents
that may enhance the anticoagulant effi-
cacy of warfarin include:
2
Alcohol: occasional large intake of alco-
•
hol is likely to enhance briefly the effects
of warfarin, but more importantly, reg-
ular immoderate intake potentates war-
farin activity, especially if liver functions
are compromised.
Analgesics:
•
Non-steroidal anti-inflammatory type
––
(NSAIDs): the anti-aggregatory effects
of the NSAIDs on platelets likely play
a major role in adding to the anti-
coagulant activity of warfarin. Their
effects are largely dose dependent,
and aspirin is a prominent offender.
It seems that meloxicam, nabume-
tone and naproxen are much less
inclined to interact in this manner. It
should be noted that extensive use
of topical NSAIDs may also enhance
warfarin efficacy.
Paracetamol, once thought to be
––
unlikely to interact with warfarin, is
now known to be a major poten-
tiator of the anticoagulant effect.
However, low, single or infrequent
therapeutic doses of paracetamol are
documented as unlikely to have any
anticoagulant-potentiating acitivity.
Opioids: propxyphene and tramadol
––
may well enhance the efficacy of
warfarin, but careful observation for
such effects on warfarin is needed
with all high-dose prolonged use of
opoids.
Anti-arrhythmics: notable in this cat-
•
egory are amiodarone, disopyramide,
propafenone and quinidine.
Antidepressants: those that are selec-
•
tive serotonin re-uptake inhibitors are
the most likely culprits from among the
antidepressant category.
Antidiabetic agents (oral): especially the
•
sulphonylurea types.
Antiplatelet agents: all chemical entities
•
with antiplatelet activity, including fish
oil concentrates and many herbal sub-
stances such as ginseng, ginkgo, aloe,
dandelion, cranberry and garlic should
be avoided.
Beta-blockers: atenolol and propranolol
•
are the most frequent offenders in
this category, but others may not be
exempt.
Fibrates: such as fenofibrate.
•
Statins: simvastatin, lovastatin and pos-
•
Take-home message
The clinical use of warfarin demands
the utmost care on the part of the
prescriber. International guidelines
recommend that an INR be done
every four weeks in patients for whom
warfarin is the key therapeutic agent,
for protection against thrombo-
embolic events.
