A man on warfarin developed gross haematuria within nine days of starting to take 400 mg

exyphebutazone daily. His prothombin time had increased to 68ns. A subsequent study on him
confirmed that the hypoprothrombinemia was due to the oxyphenbutazone. Two similar cases have
been described elsewhere. A clinical study has also shown that oxyphenbutazone slows the
clearance of discoumarol.
Oxyphenbutazone is the major metabolite of phenilbutazone within the body and it may be
presumed that the explanation for the anticoagulant/ phenilbutazone interaction equally applies to
oxyphenbutazone (see Anticoagulan + Phenilbutazone). Direct evidence of this interaction seems
to be limited to the reports cited., but it would appear to be established and of clinical importance. It
would be prudent to apply all the precautions suggested for phenylbutazone.

Anticoagulants + Paracetamol (Acetaminophent)
Abstrak
The anticoagulant effect of anisindione, discoumarol, phenprocoumon and warfarin are normally not
affected, or only increade to a small extent, by small doses of parasetamol (acetaminophen), but if
larger doses are taken reguraly a reduction in the anticoagulant dosage may be needed. There is an
isolated case of bleeding with warfarin and paracetamol.
Clinical evidence
a) Prothombin times unchange
10 patients on warfarin showed no changes in their prothombin times when given 3,0
paracetamol daily for two weeks. A further study on 10 patients given warfarin or
phenprocoumon found that two 650mg doses of paracetamol similarly had no effect on
prothombin times measured over the following 48 h.

b) Prothombin times increased
The prothombin times of 50 patients taking anisindione, discoumarol, phenprocoumon or
warfarin were incresed by an average of 3,7 s after taking 2,6 g paracetamol daily for two
weeks.
2 g paracetamol daily for three weeks incresed the thrombotest times of 10 patients on un-
named coumarin anticoagulants by approximately 20%. The anticoagulant dosage was
reduced in five out of the patients and in one of the 10 control patients.
15 normal subjects, given enough warfarin to increase their prothombin times by 1,3 s
1,50 , were additionally give 4g paracetamol daily for two weeks. The prothombin times of
seven rose by more than 20% (to 1,75) compared with one subject takin placebo, and by
more 33% (to 2,0) in fiveothers. The increases were seen from about day seven and were
maximal after 12,5 days.
An isolated report describes bleeding (haematuria, gum bleeding) in a woman on warfarin
after taking about 1,6 g paracetamol daily in a compound paracetamol-codeine preparation
for 10 days. Her prothombin time rose to 96 s. See also Anticoagulants +
Dextropropoxyphene because paracetamol is a component of Distalgesic and darvocet.

Mekanisme
Tidak diketahui

Importance and management
An established interaction although there are unexplained inconsintencies in the evidence.
The weight of clinical evidence ad common experience suggests that occasional small doses
of paracetamol (possibly up to about 2g daily) for a few days are normally unlikely to cause
important increaes in prothrombin times, but if larger amounts are taken (2-4 g daily) for
longer than a few days it would be prudent to monitor prothrombin times so that any
anticoagulant dosage reductions can be made. Anticogulants other than those specifically
cited would be expected to interact similarly. In this context paracetamol is safer than
aspirin because it does not affect platelets or cause gastric bleeding.

Anticoagulants + Penicillins
Abstrak
The effects of the oral anticoagulants are not normally altered by the penicilins but isolated
of increased prothrombin times and bleeding have been seen in patients given penicilin G,
talampicillin and ampicilllin/ flucloxacillin. Carbenicillin in the absece of an anticoagulant can
prolog prothrombin times and might therefore also do in the presence of an anticoagulant.
In contrast, a handful of cases of reduced warfarin effects have been reported with
amoxycillin, nafcillin and dicloxacilin.

Clinical evidence
a) Decreased anticoagulant effects
The prothrombin time of a patient stabilized on warfarin fell from a range of 20-25 s
down to 14-17 s (despite a doubling of the warfarin dosage) when given 12g nafcillin
daily given intravenously. A few months after the nafcillin was discontinued, the half-life
of the warfarin was found to have climbed from 11 to 44 hours. Six other cases of this
warfarin resistance with high dose nafcillin have been reported. Seven days treatment
with 500mg dicloxacillin sodium four times daily and at bedtime reduced the mean
prothrombin times of seven patients on warfarin by 1,9 s. One patient showed a 5,6 s
reduction. A very brief report states that amoxycillin caused an unspesified decrease in
prothrombin times in five patients, but by implication it was small and of limited clinical
importance.
b) Increased anticoagulant effect
Hypoprothrombinemia has been described in one patient on warfarin given 24 milion
units of penicillin G daily intravenously. Penicillin G is also known to be able to increase
bleeding times and cause bleeding in the absence of an anticoaguant. The prothrombin
time of a patient on warfarin increased when treated with amicillin and flucloxacillin,
and both bleeding and an increase in the prothrombin ratio have been described in a
patient on warfarin given talampicillin. Increases in bleeding times, bleeding and
extended prothrombin times have been described with carbenicillin in the absence of an
anticoagulant. Ampicilin, methicillin and ticarcillin are also reported to prolog bleeding
times and in theory they might also increase the effects of both heparin and the oral
anticoagulants, but reports of such interactions seem to be lacking.

Mekanisme
The nafcillin-warfarin interaction is possibly due to increase in the metabolism of
warfarin by the liver. Changes in bleeding times caused by the other penicillins appear to
result from changes in Antithrombin III activity, blood platelet changes and alterations in
the fibrinogen-fibrin conversion.

Importance and management
Documented reports of interactions between aticoagulants and penicillins are relatively
rare, bearing in mind how frequently these drugs are used. Normally no changes occur,
however individual physicians say that they have seen changes and this is reflected in a
statement in the British National Formulary which says that ...common experience in
anticoagulant clinics is that prothrombin times can be prolonged by a few seconds
following a course of broad-spectrum antibiotic e.g. ampicillin. Concurrent use should
therefore be monitored so that the very occasional and unpredicable cases (increases of
decreases in the anticoagulant effects) can be identified and handled accordingly.

Anticoagulants + phenazone (antipyrine)
Abstrak
The anticoagulants effects of warfarin are reduced by the concurrent use of phenazone.

Clinical evidence
The plasma warfarin concentrations of five patients were halved (from 2.93 to 1,41
mg/ml) and the anticoagulant effects accordingly reduced after taking 600 mg
phenazone daily for 50days. The prothrombin percentage of one patient rose from five
to 50%. In an associated study it was found that 600 mg phenazone daily for 30days
caused falls in the warfarin half-lives in two patients from 47 to 27 h and from 69 h
respectively.

Mekanisme
Phenazone is an enzyme inducing agent which increases the metabolism and clearance
of warfarin from the body, thereby reducing its effects.

Importance and management
An established interaction. The effects of concurrent use should be monitured and the
dosage of warfarin increased appropriately. Other anticoagulants may be expected to
behave similarly.

Anticoagulants + Phenothiazines
Abstrak
Chlorpromazine does not interactsignificantly with nicoumalone.

Clinical evidence, mechanism, importance and management
Although chlorpromazine in doses of 40-100mg is said to have ..played a slightly
sensitizing role.. in two out of eight patients on nicoumalone and is reported to increase
its anticoagulant effects in animals, there is nothing to suggest that special precautions
should be taken during concurrent use in man. No important interactions appear to
occur between the oral anticoagulants and other phenothiazines.

Anticoagulants + Phenylbutazone
Abstrak
The anticoagulant effect of warfarin are markedly increased by phenylbutazone.
Concurrent use should be avoided because serious bleeding can occur. Bleeding has
been achieved with both phenprocoumon and nicoumalone (acenocoumarol)
apparently achieved by careful reduction of the anticoagulant dosage.

Clinical evidence
a) Phenylbutazone added to stabilized warfarin treatment
A man, stabilized on warfarin following mitral valve replacement, was later given
phenylbutazone for back pain by his general practitioner. On admission to hospital a
week later he had epistaxis, and his face, legs and arms had begun to swell. He
showed extensive bruising of the jaw, elbow and calves, some evidence of
gastrointestinal bleeding, and a prothrombin time of 98 s.
b) Warfarin added to treatment with phenylbutazone
A man, hospitalized following a myocardial infarction, was given a single 600 mg
dose of phenilbutazone. Next day, when anticoagulation studies were done, his
prothrombin time was 12 s and he was givem 40 mg warfarin to initiate
anticoagulant therapy. Within 48 h he developed massive gastrointestinal bleeding
and was found to have a prothrombin time exceeding 100 s.
There are numerous other reports of this interaction in man involving warfarin,
phenprocoumo and nicoumalone. A single unconfirmed report describes this
interaction in two patients taking phenindione

Mekanisme
Phenilbutazone inhibits the metabolism of S (-) warfarin (the more potent of the two isomers) so
that it is cleared from the body more slowly and its effects are increased and prolonged.
Phenilbutazone also very effectively displaces the anticoagulants from their plasma protein binding
sites, thereby increasing the concentration of free and active anticoagulant molecules in plasma
water, but the importance of this latter mechanism is probably small.

Importance and management
The warfarin/ phenilbutazone interaction is very well established and clinically important. Serious
bleeding can occur and concurrent use should be avoided. Much less is known about phenidione
With phenylbutazone but it is probablyequally unsafe. Direct evidence of a serious phenprocoumon/
phenylbutazone interaction seems to be limited to two reports, and there is good evidence that
successful and apparently uneventful concurrent use is possible, presumably because the response
and the anticoagulant dosages carefully controled. A study in 357 patients given 600 mg
phenylbutazone to which was added nicoumalone (acenocoumarol) from day five onwards found
that 25% less nicoumalone was needed than in control group on nicoumalone alone. Evidently
concurrent their use is possible. Information about other anticoagulants is lacking, but until there is
clear evidence to the contrary expect them to behave like warfarin. Remeber too that
phenylbutazone effects platelet aggregation and can cause gastrointestinal bleeding, whether an
anticoagulant is present or not. Alternative non-interacting NSAIDs include ibuprofen and naproxen.