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19 Commonly Prescribed Medications that Aect Clotting: AComprehensive Overview
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prosthetic heart valve, stroke, deep venous thrombosis (DVT),
pulmonary embolism (PE), or antiphospholipid syndrome.
Warfarin exists as two optically active isomers, R and S,
which are highly protein-bound (99%). Oral bioavailability
is around 90%. Warfarin is metabolized by oxidative metabolism in the liver, which involves several cytochrome P450
isoenzymes; the elimination of warfarin is almost entirely by
hepatic microsomal enzyme metabolism. S-Warfarin is ve
times more potent than R warfarin and is metabolized primarily by CYP2C9, while R- warfarin is metabolized primarily by CYP2C19, CYP1A2, and CYP3A4. Certain
individuals carry allele variations of CYP2C9, which reduces
the rate of warfarin metabolism. These variations are estimated to occur in up to 11% of the Caucasian population.
Warfarin half-life ranges from 25 to 60h (mean – 40h), and
duration of effect can be 2–5days [76].
Warfarin has a narrow therapeutic index and variable dose
requirements. This combination of variable dose requirements, and variable rates of metabolism and clearance makes
it difcult to maintain patients within a dened range of anticoagulation. Maintaining the patient in the ideal INR target
range of greater than 2 but less than 3 is challenging; an INR
of less than 2 increases the risk of thrombotic events, while
INR greater than 3 increases the risk of bleeding [39]. These
bleeding events can range from ecchymosis, occult bleeding,
or hemorrhage and from upper or lower gastrointestinal tract,
microscopic or macroscopic hematuria, epistaxis, or intracranial hemorrhage. The use of warfarin has the highest fatal
intracranial bleeding risk when the risk is compared to the
newer DOAC medications [42]. Additionally, warfarin
administration carries associated risks of teratogenicity, cholesterol embolization, vascular calcication, nephropathy,
and skin necrosis in patients with protein C deciency. On
the other side of the spectrum, subtherapeutic INR can result
in life-threatening thromboembolic events.
Similar to concerns with the use of other anticoagulant
agents, contraindications to use of warfarin include active
bleeding, severe thrombocytopenia (dened as platelet count
<50,000/L), signicant trauma, invasive procedures, obstetric delivery, history of intracranial hemorrhage, intracranial
or spinal tumor, administration of neuraxial anesthesia, and
severe, uncontrolled hypertension. Other contraindications
that are more specic to warfarin include thyroid disease and
renal insufciency [39]. Patients who are beginning warfarin
therapy; usually start with 5 mg daily on days 1 and 2 of
therapy; then on day 3, the dose is usually adjusted based on
results of PT/INR.Patients who are elderly, frail, malnourished, or with preexisting liver, heart, or kidney disease usually use 2.5mg daily or 2.5mg alternating with 5mg daily
[59]. Several factors affect the warfarin dose, including age,
body mass index, gender, race, concomitant drug use, comorbidities, and genetic variables that affect warfarin pharmacokinetics and pharmacodynamics. Saleh et al. have
proposed application of articial neural network (ANN) to
develop a warfarin dosing algorithm, and they were able to
predict ideal warfarin dosage in 48% of patients [77].
Heparin
Unlike the other oral and IV anticoagulants discussed previously, which do not depend on antithrombin activity to provide anticoagulation effects, heparin is an
antithrombin-dependent, indirect Factor Xa inhibitor [60].
Heparin may be administered via the subcutaneous or intravenous route, but it is not administered via an oral route.
Indications for the use of heparin include prophylaxis and
treatment of thromboembolic disorders (VTE, PE) and
thrombotic complications associated with atrial brillation,
prevention of clotting during vascular and cardiac surgery,
and as an anticoagulant for extracorporeal circulation and
dialysis procedures. Contraindications of heparin include
hypersensitivity to heparin, severe thrombocytopenia, history of heparin-induced thrombocytopenia (HIT), and
uncontrolled active bleeding except when that bleeding is
due to diffuse intravascular coagulation (DIC) [66]. Initiation
of heparin anticoagulation often starts with an initial bolus of
80units/kg followed by 18units/kg/hr as a therapeutic dose
or 5000 units subcutaneously 2 h preoperatively and then
every 8–12h postoperatively as a prophylactic dose [78].
Side effects associated with heparin use include thrombocytopenia, HIT, chest pain, shock, thrombosis, vasospasm,
hemorrhage, and increased liver enzymes [66]. Unlike warfarin, heparin does not cross the placenta, so when anticoagulation is needed during pregnancy, it is considered to be a
more useful anticoagulation medication and associated with
a signicantly reduced risk. Heparin can be used for treatment of thromboembolic disease during pregnancy [65].
Warfarin, heparin, and the newer DOACs may be used to
provide prophylaxis against and treatment of major thromboembolic complications that may arise in the peri-operative
period. While these medications each have specic side effects,
common to all anticoagulants is the risk of major bleeding.
Since patients who are using any of these anticoagulation medications are often concurrently taking medications that can
affect the metabolism of anticoagulants, they often have an
increased risk of experiencing adverse events. Clinicians who
prescribe these medications or administer them should be wellinformed about the various drug-drug interactions that exist.
Interactions that occur between anticoagulants and antidepressants, antiplatelets, antibiotics, NSAIDs, and herbal supplements are clearly documented [60–63, 78].
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Drug-Drug Interactions: Drug Classes
Antidepressants and SSRIs
Warfarin is metabolized by the cytochrome P450 enzymes.
One of these enzymes, cytochrome P450 2C9 (abbreviated
as CYP2C9), demonstrates a major role in the oxidation of
xenobiotic and endogenous compounds. This enzyme is
inhibited by the antidepressants uoxetine and uvoxamine. Whenever a patient using one of these antidepressants also has warfarin administered, the warfarin is not
metabolized as efciently. This leads to increased warfarin
levels and enhanced warfarin effects. Other antidepressants, such as citalopram, nefazodone, and sertraline, have
not demonstrated such associations with warfarin [69].
Similarly, a severely elevated INR was found with the concomitant use of duloxetine and warfarin. This was hypothesized to be the result of metabolism by various cytochrome
P450 enzymes or competitive binding of both substances at
protein-binding sites [63].
Antiplatelet Drugs
Several studies have demonstrated that combining antiplatelet drugs and anticoagulants can lead to detrimental
synergistic reactions that ultimately lead to increased
bleeding. One such example is detailed in a paper by So
and Eckman; they state, “multiple studies examining outcomes of combined antiplatelet and anticoagulant therapy
in patients with indications for both have demonstrated an
increased risk of major hemorrhage compared with either
treatment alone” [79]. Similarly, a meta-analysis of 25,307
patients demonstrated that the combination of antiplatelets
and anticoagulants in individuals with ACS does not
reduce major adverse cardiac events (MACE), such as allcause death, nonfatal MI, and nonfatal thromboembolic
stroke, but it does increase the risk of major bleeding. Due
to the negative clinical outcomes associated with concomitant use of full-dose warfarin and aspirin, this combination
is not preferred for long-term treatment of coronary artery
disease or peripheral artery disease [63]. “Medications
affecting platelet function have a synergistic pharmacody-
namic interaction with warfarin; concomitant use, therefore, can result in signicant increases in PT-INR and, in
turn, in an increased risk of bleeding” [68]. A study done
in 278,074 Australian veterans who had been using warfarin demonstrated that approximately 7.2% received coadministration of nonsteroidal anti-inammatory agents
and 5.9% received antiplatelet medications such as
NSAIDs. This study, however, did not assess harm associated with these potentially hazardous interactions and
noted that their study could not assess concomitant purchase of over-the-counter medications such as aspirin and
some NSAIDs [80].
Antibiotics
Antibiotics, like antidepressants, are heavily metabolized by
CYP450 enzymes, most notably CYP3A4, and have also
been found to interact with permeability glycoproteins.
Because many anticoagulants interact with both CYP3A4
and permeability glycoproteins, drug-drug interactions may
arise and affect the metabolism of these drugs. Notably, the
bioavailability of dabigatran is decreased with concurrent
use of clarithromycin and rifampicin. Clarithromycin, erythromycin, uconazole, and ketoconazole affect the bioavailability of rivaroxaban. Because apixaban and edoxaban are
newer drugs, less drug-drug interaction data is available [62].
As detailed in a table from Minno etal., plasma DOAC concentrations can be increased with concurrent use of common
antifungals and antibiotics due to inhibition of permeability
glycoproteins (P-gp) and CYP450 enzymes [68]. Those that
inhibit P-gp and CYP3A4 are the “-conazole” antibiotics:
ketoconazole, itraconazole, voriconazole, and posaconazole.
those that inhibit P-gp and CYP450 are the “-mycin” antibiotics: erythromycin, clarithromycin, and azithromycin.
NSAIDs
A synergistic effect, which led to increased bleeding, has
been noted with the concomitant use of NSAIDs and warfarin. Other commonly used anti-inammatory drugs, such as
acetaminophen, allopurinol, celecoxib, dextropropoxyphene,
indomethacin, methyl-prednisolone, piroxicam, sulindac,
and tramadol, were all found to increase PT/INR, while
mesalazine and sulfasalazine lowered PT/INR [68]. Adverse
drug-drug interactions have been noted to occur between
NSAIDs and a variety of concomitantly administered medications such as aspirin, alcohol, some antihypertensives,
antidepressants, and other commonly used medications [81].
Herbal Supplements/Ginkgo
Like medications discussed previously, many herbal supplements have drug-drug interactions with anticoagulants and may,
therefore, contribute to increased bleeding risks. Comparedto
vitamin K antagonists, such as warfarin, DOAC effects have
proven to be more stable and less inuenced by herbal supplements or differences in diet [68]. Additionally, the quantity of
herbal supplements taken by patients already taking warfarin
also inuences therisk of bleeding; Chan etal. found that “warfarin patients taking no herbal medications or only 1 herbal <4
times per week were more likely to have PT-INR values within
the optimal therapeutic range of 2.0–3.0 compared to those taking >1 type of herbal ≥4 times per week (58.1% vs 51.1%,
P = 0.046)” [60]. Consumption of Ginkgo can also increase
the risk of bleeding; in vitro studies have shown that avanol
aglycones like amentoavone, which are components of Ginkgo,
can inhibit CYP2C9 and thereby increase plasma concentrations
of anticoagulants metabolized by this enzyme [68].
19 Commonly Prescribed Medications that Aect Clotting: AComprehensive Overview
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Drug-Drug Interactions: Specic Drugs
Amiodarone
Since warfarin is used to prevent or reduce the risk of stroke
in patients with atrial brillation, prosthetic valves, and
patients with a history of thromboembolic disorders, both
amiodarone and warfarin have been used concurrently. When
concerns of ventricular or supraventricular arrhythmias exist,
amiodarone (as a Vaughan-Williams class III antiarrhythmic
agent with a long half-life) may be administered concurrently with warfarin. It is essential to be aware of the resulting interactions when a patient uses both of these medications.
Amiodarone is metabolized by CYP3A4 and CYP2C8 to
desethylamiodarone, and these hepatic enzymes are also
involved to some extent in warfarin metabolism. Amiodarone
decreases CYP2C9 1A2 and 3A4 enzymes and thereby
inhibits warfarin hydroxylation [82–84]. This reduces clearance of the more potent S- warfarin. In patients receiving the
drug combination of amiodarone and warfarin, the anticoagulation effect is increased from this reduction in hepatic
clearance whenever both drugs are administered.
Anticoagulation is potentiated since the dose of warfarin
required to achieve a therapeutic INR is reduced. Some studies have also suggested altered protein binding as a contributor to this effect.
Multiple factors affect these interactions, such as the
patient’s specic genetics, and the presence of comorbidities
from cardiac, hepatic, or renal systems, thyroid dysfunction,
GI bleed, or cancer. The specic interactions affecting the
rate of metabolism and clearance may also relate to specic
other medications used. Theseinteractions are patient specic and not clearly predictable. Advanced patient age may
also reduce the clearance of both medications and increase
the potential for adverse interactions.
Drug interaction between warfarin and amiodarone results
in apotentiation of warfarin’s effect and prolonged INR due
to prolonged half-life. In a Swedish retrospective study conducted by Holm etal., more than one in three patients receiving both warfarin and amiodarone revealed supratherapeutic
anticoagulative effect within 3weeks to an INR of around
3.07 [82].
There is an increased bleeding risk when a patient uses
both amiodarone and warfarin. After initiation of amiodarone, close monitoring of INR once every 3–4days to maintain therapeutic level of anticoagulation, and timely dose
adjustment, is vital to prevent life-threatening bleeding episodes and thus hospitalizations. A study by Sanoski etal. to
determine the dosage relationship in patients on long-term
amiodarone indicates that the magnitude of interaction peaks
at 7 weeks and is associated with a 44% mean maximum
reduction in warfarin dose; the warfarin requirement gradually increased thereafter. Additionally, they report that the
interaction is dependent on the maintenance dose of amiodarone [83]. Lam et al., in a retrospective study on older
patients found a greater risk of hemorrhage among patients
who received amiodarone compared with patients receiving
warfarin alone and encountered mortality of 12.5% following initiation of amiodarone [85].
When initiating amiodarone therapy, there are manyrecommendations. Holm etal. recommend an initial reduction
of the mean dose of warfarin by 25% [82]. A study by
Sanoski recommends reducing dose of warfarin by 40%
when using 400 mg/d of amiodarone and additional 55%
reduction in warfarin dose when amiodarone dose is tapered
to achieve INR of 2–3 [83]. Family practice physicians were
cautioned about the interaction between amiodarone and
warfarin in 2002; a percentage reduction in the administered
warfarin dose based on the administered amiodarone dose
was recommended [86]. Carpenter et al. suggested an
empiric warfarin dose reduction of 30–50% upon initiation
of amiodarone and weekly INR monitoring [84].
Ciprooxacin (Cipro)
In a population-based study, Fischer etal. stated that concomitant use of warfarin and ciprooxacin in older patients
increased the risk of hospital admission with upper gastrointestinal hemorrhage [87]. Lane and colleagues found that
42.6% of antimicrobial prescriptions among warfarin users
were for medications (TMP/SMX, ciprooxacin, levooxacin, metronidazole and uconazole) that presented risk for
excessive bleeding [88].
A study of all 66 cases reported to the FDA spontaneous
reporting system (SRS) database from 1987 through 1997,
including the two that occurred at his institution, Ellis etal.
report that patients previously anticoagulated with warfarin,
who have ciprooxacin administered, may develop an exaggerated hypoprothrombinemic response and bleeding diathesis. In 50 of these patients, this coagulopathy was recognized
within 5.5days following initial administration of ciprooxacin. The ciprooxacin–warfarin coagulopathy occurred
most commonly in patients in their seventh decade of life
and in those who required polypharmacy. Additionally, they
reported a more rapid resolution of the coagulopathy when
the patients received active treatment for the coagulopathy,
rather than simply withholding the medications involved and
keeping the patients under medical observation while the
coagulopathy spontaneously resolved. This study by Ellis
suggests that INR should be checked within 4–5days following initiation of ciprooxacin, especially in older patients
[89].
Clarithromycin (Biaxin)
Clarithromycin is a macrolide antibiotic. As described by
Lane etal., this drug is a high-risk antibiotic that interacts
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with warfarin and increases the risk of serious bleeding that
requires hospitalization [90]. Clarithromycin inhibits warfarin metabolism particularly via CYP3A and P-glycoprotein.
It may also eliminate vitamin K-producing bacteria in the
intestines to further alter the therapeutic effect of warfarin
and prolong the international normalized ratio (INR). INR
monitoring is essential within 3–14days of the prescription
to reduce the risk of serious bleeding event. A case report
published in Emergency Medicine Journal, 2006, reports a
case of retroperitoneal hematoma in a 69-year-old woman
who had been on chronic warfarin and was prescribed clarithromycin for lower respiratory infection [91].
Erythromycin, and Quinidine
Both erythromycin and quinidine are known to affect cytochromes P1A2 and P3A4. Al-Jundi and Rubin have described
a rare presentation of spontaneous hemopericardiac tamponade in a patient on warfarin who was treated with erythromycin for a chest infection [92].
Rifampin (Rifadin, Rimactane)
Administration of rifampin is known to induce CYP2C9 and
CYP3A4, and it therefore increases clearance of warfarin.
This may result in a decrease of the INR, unless the dose of
warfarin is concomitantly increased by 25–40% when therapy with rifampin is initiated. Poon etal. reported a warfarinrifampin drug interaction in a 20-month-old- female where the
warfarin management posed a challenge due to dramatic
increase in warfarin dosing requirement [93].
Metronidazole (Flagyl)
Metronidazole decreases CYP2C9 activity and therefore
interferes with metabolism of S-warfarin. This results in an
increase in the INR when metronidazole is added to the medications a patient takes, when the patient is using warfarin.
This increased INR is likely to be clinically important as the
risk for intracranial hemorrhage doubles for each 1.0 increase
in the INR.Even if intracranial hemorrhage does not occur,
it appears that the risk for other minor bleeding complications increases. It is recommended that the warfarin dose
should be reduced by 25–40% when metronidazole (Flagyl)
therapy is initiated [94]. A retrospective study by Holt etal.,
recommends 30–35% reduction in mean daily dose (a preemptive dose reduction) to maintain therapeutic anticoagulation while on metronidazole. However, while considering a
preemptive dose reduction of warfarin, the risk of subtherapeutic INR and risk of thromboembolic events should be
weighed against risk of bleeding. INR should be monitored
no later than 72h after initiation of both medications in such
instances where risk of thromboembolism is high [94].
Trimethoprim/Sulfamethoxazole (Bactrim)
Bactrim is apotent antimicrobial thatinteracts with warfarin.
Antimicrobials can inhibit CYP450 isozymes, alter protein
binding, and alter the gut ora, thereby reducing vitamin K
absorption. Several studies illustrate that this drug signicantly and rapidly elevates INR in patients taking warfarin
and signicantly increases risks of undesired bleeding, especially in elderly patients. Concomitant use of warfarin and
cotrimoxazole was discussed in the Annals of Internal
Medicine in 2010. This article clearly states that few drug
interactions are as well established as the interactions
between these two medications. These interactions were felt
to markedly increase risk of upper GI hemorrhage, which
qualies as a “never event” by the National Quality Forum
95]. Bactrim decreases CYP2C9 activity; this is primarily
[
due to the sulfamethoxazole component, rather than from trimethoprim. Concurrent use of warfarin and trimethoprim/
sulfamethoxazole is associated with two to vefold increase
in bleeding risk [96]. When initiating bactrim therapy in a
patient who is also using warfarin, the INR should be monitored within 3–4 days of starting the antimicrobial. When
bactrim is initiated, the recommended dose reduction of warfarin is by 10–20% to avoid potentially dangerous increase in
INR prior to the INR follow-up [
slower due to longer half-life of warfarin. It is equally important to adjust the warfarin dose once the antimicrobial is discontinued to avoid subtherapeutic INR. Fischer et al.
recommend that in older patients receiving warfarin, it is better to prescribe alternative antibiotics as patients are at high
risk for upper GI hemorrhage when cotrimoxazole is administered along with warfarin [87].
97]. Dose titration should be
Fluvastatin (Lescol)
HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A)
reductase inhibitors are effective in both primary and secondary prevention of ischemic heart disease. Since they are
usually prescribed in older patients for a prolonged duration,
the drug interactions must always be borne in mind.
Fluvastatin is a synthetic HMG Co-A reductase inhibitor and
a lipid-regulating drug. Patients with cardiovascular disease
are often prescribed warfarin and statins concurrently. In an
investigation of the interaction between the two, it was found
that uvastatin signicantly displaced the plasma protein
binding of warfarin [98]. Fluvastatin inhibits CYP2C9 and
the formation of 7-hydroxy warfarin. This increased warfarin
concentrations and increased bleeding risk. Other “statin”
medications, lovastatin, rosuvastatin, and simvastatin, exert a
similar effect. Although the combination therapy of a “statin”
and warfarin is frequently considered useful, the INR should
be closely monitored after initiation therapy or a change in
the dose of the medication.
Atorvastatin (Lipitor)
Another HMG-CoA reductase inhibitor is often prescribed
for both primary and secondary prevention of ischemic heart
disease. Since this class of medications is usually prescribed
in older patients for a prolonged duration, the drug interac-
19 Commonly Prescribed Medications that Aect Clotting: AComprehensive Overview
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tions must always be borne in mind. In addition to the interactions already noted that occur with this class of medications,
atorvastatin inhibits CYP3A4 isozymes, which metabolizes
the less active R isomer and creates the same concerns noted
previously with use of itraconazole (Sporanox). An observational study by Schelleman etal. reported that initiation of
statins in chronic warfarin users increases the potential risk
of gastrointestinal bleeding, especially during the rst antihyperlipidemic prescription [99]. A case report in the British
Journal of Hospital Medicine describes the rare event of
acute rhabdomyolysis following initiation of warfarin in a
patient on stable atorvastatin therapy [100]. The mechanism
of this appears to be that warfarin administration increased
the bioavailability of the statin, resulting in acute rhabdomyolysis. Close monitoring of INR, serum creatine kinase levels, and constant vigilance is required when these drugs are
co-prescribed as there is potential for increased bioavailability of either drug.
Carbamazepine (Tegretol)
Carbamazepine is an antiseizure medication of the iminostilbene class, indicated for use in the management of temporal
lobe epilepsy/complex partial seizures. Additionally, carbamazepine has been used as a rst-line medication for trigeminal neuralgia. It enhances warfarin metabolism by induction
of the cytochrome P450 group, primarily CYP2C9 and
CYP3A4. A Swedish retrospective study reports that patients
on warfarin who were co-administered carbamazepine experienced a subtherapeutic anticoagulation effect within
3–5 weeks. The average warfarin dose was subsequently
increased by 49.2% (95% CI 42.8–55.9) to maintain the
desired level of anticoagulation [101]. Clarke et al. also
found that warfarin dose requirement increased by 32% after
carbamazepine initiation. The onset of interaction with warfarin was chronic and with a variable onset ranging from 16
to 30days in this study. Therefore, the authors did not make
a recommendation for a predicted preemptive dose adjustment [102].
Close INR monitoring is essential when carbamazepine is
initiated or withdrawn during warfarin therapy, to meet the
anticipated change in dose demand and to prevent ischemic
stroke and thrombosis.
Fluvoxamine (Luvox)
Concomitant use of uvoxamine or other selective serotonin
reuptake inhibitors (SSRIs) and warfarin is very common, as
cardiovascular disease and depression often coexist. In theory, SSRIs could inhibit platelet aggregation by preventing
platelet reuptake of serotonin. Fluvoxamine maleate has the
potential to inhibit multiple cytochromes (CYP1A2,
CYP2C9, CYP2C19, and CYP3A4) to a signicant degree.
It is a potent CYP2C9 inhibitor with a half-life of 17–22h
after a single dose. This is an important consideration
because CYP2C9 is the main metabolizing enzyme of the
more active (S)- enantiomer of coumadin. This would appear
to increase the risk of excessive anticoagulant effect of warfarin when these medications are co-administered.
A multi-database cohort study by Dong et al. followed
52,129 patients for up to 180days and analyzed the bleeding
and thromboembolic events and mortality in patients exposed
to SSRIs and warfarin. They concluded that patients concomitantly treated with warfarin and SSRIs that are potent
CYP2C9 inhibitors had comparable rates of bleeding events,
ischemic or thrombotic events, and mortality. This study suggests that SSRI inhibition of CYP2C9 does not appear to
affect major safety or effectiveness outcomes of warfarin
treatment in clinical practice, where patients may be closely
monitored [
pharmacokinetic interaction than expected, and hence minimal effects on clinical outcome, could be upregulation of
other enzymes that metabolize warfarin.
In contrast to the Dong study however, a few years prior
to its publication, Quinn etal. reported that SSRI exposure
was associated with major hemorrhage risk in patients taking
warfarin [
described an increased risk of intracerebral and intracranial
hemorrhage with concomitant use of SSRI and oral anticoagulants when compared to patients with oral anticoagulants
alone [105]. It would certainly appear that caution is advised
when managing patients using both SSRI medications and
warfarin, even though there may be no clear “cause and
effect” relationship.
103]. A possible explanation for less impact on
104]. Almost 2years earlier Hackam et al. also
Fluoxetine (Prozac)
Fluoxetine is a selective serotonin reuptake inhibitor, which
ranks 14th on the list of medications used concomitantly
with warfarin [76]. Fluoxetine hydrochloride is a potent
CYP2C9 inhibitor and inhibits oxidative metabolism of
S-warfarin. This drug has high afnity for plasma albumin.
SSRIs might hinder platelet aggregation by depletion of
platelet serotonin levels and could result in an increased therapeutic response and an increase in INR. Recognizing the
narrow therapeutic index of warfarin, and the potential for
multiple medications used in psychiatry to interfere with it,
an analysis of data published in 2009 recommended that
while uvoxamine and uoxetine pose the highest potential
risks, sertraline and citalopram appear to be the safest antidepressant medications to use in patients who concomitantly
use warfarin [106].
Itraconazole (Sporanox)
Itraconazole is a broad-spectrum triazole antifungal agent
for prophylaxis and treatment of aspergillosis, endemic
mycoses, onychomycosis, and vaginal candidiasis. It
inhibits CYP3A4, which metabolizes R (+) warfarin (the
less biologically active enantiomer of warfarin) and
P-glycoprotein, and therefore, interactions are less severe
than other azole antifungals [107]. It is recommended to
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monitor for increased anticoagulant effects (e.g., INR,
bleeding) if itraconazole is initiated/dose increased, and
decreased effects if itraconazole is discontinued/dose
decreased [107].
Fluconazole (Diucan)
Fluconazole inhibits the metabolism of S-warfarin via
CYP2C9 and 8-hydroxylation of R-warfarin through
CYP2C19 [108]. UpToDate recommends empiric reduction
in warfarin dose of 10–20% along with INR monitoring for
dosing titrations [109].
Miconazole (Monistat)
Miconazole is a broad-spectrum antifungal agent and is the
strongest inhibitor of CYP2C9 and CYP2C19, followed by
voriconazole and uconazole. Due to the strong inhibition of
CYP2C9 and therefore, inhibition of the conversion of (S)
warfarin to (S) 7-hydroxywarfarin, PT-INR increases [108].
Elderly patients on warfarin usually have comorbidities and
increased risk of oral candidiasis. Systemic absorption after
topical administration decreases total body clearance of both
(R) and (S) warfarin. A study reports the pro-hemorrhagic
effects of ecchymosis, subcutaneous hematomas, and hematuria aftertwoweeks of concomitant use with warfarin [68].
Another case report describes intestinal intramural hematoma presenting as acute abdomen after initiation of topical
miconazole for vaginal candidiasis [110]. In patients using
warfarin, nystatin appears to be a safer choice for oral candidiasis treatment [111].
Voriconazole (Vfend)
Voriconazole is a triazole with broad-spectrum antifungal
activity. It is metabolized by CYP450 enzymes, primarily by
CYP2C19, CYP2C9, and CYP3A4 [108]. It is also a strong
inhibitor of CYP3A4. The (S) form is the more pharmacologically active isomer. Since the CYP2C9 pathway is
involved in its metabolism, the interactions with anticoagulation medications are clinically signicant. This involvement
results in a prolongation of the prothrombin time. Purkins
etal. performed a double-blind randomized controlled study
and noted that voriconazole potentiates warfarin-induced prothrombin time prolongation. Without a reduction in warfarin
dose, the peak anticoagulation effect at 40–50h following a
voriconazole dose appears to be approximately 50% greater.
This enhanced anticoagulation effect can still be seen even at
144 h following co-administration with voriconazole. They
recommended regular monitoring of the prothrombin time if
voriconazole and warfarin are co-administered [112].
of anaphylaxis (SRSA). Cysteinyl leukotriene production
and receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth muscle constriction, and altered cellular activity associated with
the inammatory process, which contribute to the signs and
symptoms of asthma. In vitro studies demonstrated that
Zarlukast antagonized the contractile activity of three leukotrienes (LTC
, LTD4,, and LTE4) in conducting airway
4
smooth muscle from laboratory animals and humans. It also
prevented intradermal LTD4-induced increases in cutaneous
vascular permeability and inhibited inhaled LTD4-induced
inux of eosinophils into animal lungs. In humans, zarlukast inhibited bronchoconstriction caused by several kinds of
inhalational challenges. The bronchodilation, antiinammatory properties, and steroid-sparing effects provide
signicant benets to patients with allergic and exerciseinduced asthma. Pretreatment with single oral doses of zarlukast inhibited the bronchoconstriction caused by sulfur
dioxide and cold air in patients with asthma. It usually takes
weeks before maximal benet is seen when this class of
medication is administered. As such, these medications are
primarily used for prophylaxis and treatment of allergic and
exercise-induced asthma. Zarlukast exhibits a peak plasma
concentration within 3h after oral administration and exhibits a plasma protein binding of >99% to albumin. Its mean
terminal elimination half-life is ~10h. It is cleared by hepatic
metabolism involving hydroxylation by the CYP450 system,
primarily utilizing CYP2C9. In vivo studies have demonstrated that zarlukast inhibits CYP3A4 and CYP2C9 isoenzymes [113]. In patients with signicant hepatic impairment
(e.g., biopsy proven cirrhosis), there is a reduced clearance
resulting in 50–60% greater maximum concentration and a
prolonged area under the curve in clearance studies, when
compared to normal subjects [114]. If co-administered to a
patient on warfarin therapy, Zarlukast impairs the normal
clearance of warfarin, and enhanced antithrombotic effects
result. This is demonstrated by an increase in PT and INR
values demonstrated on coagulation studies.
Cimetidine (Tagamet)
Use of cimetidine does not appear to be of signicant concern to patients taking warfarin. The cytochrome isoenzymes
involved in cimetidine metabolism, CYP1A2 and CYP3A4,
are primarily involved in the metabolism of the less potent
R-warfarin isomer. Interactions and inhibition of metabolism
are usually of less magnitude than when co- administered
medications affect the CYP2C9 isoenzyme.
Zarlukast (Accolate)
Zarlukast is a selective peptide leukotriene receptor antagonist of three leukotriene C4, D4, and E4 (LTC4, LTD4 and
LTE4), which are components of the slow-reacting substance
Patients withHIV Infections
Patients who suffer from HIV are prone to venous thrombosis. Antiretroviral drug interactions are mediated through the
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cytochrome P450 pathway and through P-glycoproteins to a
lesser extent. Anti-HIV medications are protease inhibitors
and therefore demonstrate inhibition of the cytochrome P450
system; they also tend to induce CYP2C9. This tends to
enhance themetabolism of warfarin. The extent of this effect
and the specic CYP450 isoenzymes involved vary from one
anti-HIV medication to another. The INR response from
the administration of any of these medications should be
monitored when a patient is also using any anti-HIV medications concurrent with theuse of anticoagulation medications.
Indinavir (Crixivan)
Indinavir is a protease inhibitor and an inhibitor of CYP3A4.
Even though indinavir demonstrates mild to moderate
hepatic impairment, there is less concern about excessive
inhibition of warfarin metabolism when indinavir is coadministered, because the CYP2C9 isoenzyme is not
involved.
Ritonavir (Norvir)
Liedtke and Rathbun found that intermittent ritonavir use
may result in inhibition of CYP2C9 and CYP3A4, rather
than induction [115].
their high protein binding and their cytochrome P450 dependent clearance mechanism. Additionally, they also have antiplatelet effects. NSAIDs may cause gastric ulcers by erosion
of the stomach lining and increase the risk of signicant gastrointestinal bleeding when the anticoagulant effect of warfarin is superimposed. Yildirim et al. have described a rare
complication in an 80-year-old female on stable chronic warfarin therapy for the previoustenyears and who was tested
regularly for anticoagulation status. Her last INR values
prior to this emergency presentation had been 2.1. Following
use of a non-steroidal anti-inammatory medication for
arthritis painthreedays earlier, she presented to the emergency department with complaints of the sudden onset of
severe abdominal pain but had not noted melena or hematochezia. CT evaluation demonstrated ndings of distal jejunum and proximal ileal transmural thickening along with
extensive free peritoneal uid. During her observation in the
emergency department, her hemoglobin level dropped to 3g/
dL and she developed hemorrhagic shock, despite no clear
evidence of external bleeding or intraluminal intestinal
bleeding. On admission, she had a prothrombin time of
68.9s and INR of 12. She was given fresh frozen plasma,
vitamin K supplements, and red blood cells to normalize
INR and hemoglobin level [118].
Prednisone (Deltasone, Sterapred, Preds, Etc.)
Prednisone is a frequently used anti-inammatory agent.
Prednisone and warfarin have been used together in idiopathic
hypereosinophilic syndrome (IHES), a rare disease associated
with cardiac thrombosis and endocardial wall thickness. They
are also prescribed together in the management of peripheral
vascular disease associated with autoimmune disease, systemic lupus erythematosus (SLE), multiple myeloma, Behcet’s
disease, etc. Case reports indicate an increased INR response
afterthe addition of prednisone to warfarin [116].
A randomized controlled trial by Dowd etal. compared a
10–20% preemptive dose reduction vs. a reactive adjustment
and found that the preemptive warfarin dose reduction resulted
in a nonsignicant reduction in supratherapeutic INR but, contrary to expectations, increased the chances of subtherapeutic
INR [117]. These studies demonstrate that an increase in INR
within 3–10 days after corticosteroid initiation may be
expected. Timely INR monitoring is essential when these two
medications are co-prescribed. A therapeutic dose adjustment
may be expected but should be based on INR response.
Nonsteroidal Anti-inammatory Drugs
(NSAIDs)
NSAIDs are commonly used to control musculoskeletal
pain. NSAIDs are known to interact with warfarin due to
Chronic Ethanol Use or Abuse
Chronic ethanol ingestion increased warfarin clearance via
induction of CYP2E1, while acute ethanol use inhibits warfarin metabolism.
Vitamin K
Many foods contain signicant amounts of vitamin K. The
average person in the United States takes in 60–80 micrograms (mcg) of vitamin K per day. Dietary vitamin K can
alter the effectiveness of warfarin. Consistency in dietary
intake of food containing high amounts of potassium is also
important for patients on warfarin. Dietary supplements that
contain vitamin K or metabolites related to vitamin
K-coenzyme Q10 have the potential to reduce the effects of
warfarin. Other dietary constituents which may affect a
patient’s coagulation status, especially when using anticoagulation medications, include weight-loss diets (rich in
green vegetables), multivitamins/dietary supplements, broccoli, brussels sprouts, cabbage, collard greens, endive, kale,
lettuce, mustard greens, parsley, spinach, swiss chard, turnip
greens, watercress, lentils, garbanzo beans, soybeans, soybean, canola oil, olive oil, liver (from beef, pork, or chicken),
avocados, dried basil, thyme, oregano, dill pickle, green
peas, foods packed in oil, snack foods fortied with vitamin
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K, grapefruit, grapefruit juice (the component furanocoumarin in grapefruit and grapefruit juice decreases warfarin
metabolism by inhibiting CYP3A4), store-bought margarine, store-bought mayonnaise, and store-bought salad dressings (due to vegetable oil content).
St. John’s Wort (Hypericum perforatum)
Herbal supplements, which are not FDA-approved medications can often be overlooked. It is not always easy to elicit
the history of ingestion of herbal supplements from the
patients, as they might mistakenly think that they are herbs
and hence innocuous. Herbs have the potential to cause
adverse effects when used concomitantly with medications
as they contain bioactive compounds. Patients should be
educated regarding the possible interactions, risks, and consequences with drugs and supplements. St. John’s Wort is
notably used for depression, sleep disorders, anxiety, and
pain. It is documented to interact with 147 medications
[119]. Its decreases theplasma concentration of warfarin by
inducing CYP2C9 and CYP3A4 [120, 121]. This increases
the clearance of both R and S enantiomers of warfarin. Thus,
concurrent use of St John’s Wort reduces the efcacy of warfarin, putting the patient at a greater risk for a decrease in the
INR and the development of a thrombotic event.
In summary, many drug-drug interactions between anticoagulants and other medications exist, and careful consideration of these interactions is recommended during the
peri-operative period. If physicians are not diligent about
attention to detail, serious, avoidable complications related
to excessive or inadequate anticoagulation may arise.
When considering them as a group, anticoagulants are an
exceptional class of medications that help to provide lifesaving prophylaxis and treatment for thromboembolic
events. Many individuals are prescribed anticoagulation for
the remaining duration of life. Without these medications,
complications such as blood clots, DVTs, PEs, and strokes
would be much more common and would have much higher
mortality rates. Anticoagulants are effective, cost-efcient,
and used all over the world. However, risks of side effects
and other adverse effects are associated with the use of medications, which provide anticoagulation effects. Many drugdrug interactions exist, which may adversely impact the safe
and effective use of these medications. Due to the often fastpaced and trauma-associated nature of their specialties, anesthesiologists and physicians working in Emergency Rooms
should be well-informed about potential risks associated
with the various medications, which have anticoagulation
properties. When using anticoagulation medications, patients
should keep readily found information with them (e.g.,
Medic-Alert bracelets or other identication cards), which
will quickly alert medical personnel to use of these agents.
Proper management by medical personnel can be achieved
only when they readily know, which anticoagulant medication, or combination of anticoagulation medications, is being
used.
Antibrinolytics
Under normal physiologic conditions, both the coagulation
and brinolytic systems are intimately related allowingfor
balanced hemostasis. Fibrinolysis is a tightly controlled
enzymatic process that is responsible for blood clot regulation and breakdown. These processes are regulated by a vast
array of receptors, inhibitors, and cofactors [122]. Fibrin is a
central component and serves asthe main conduit for both
thrombus breakdown and formation. Plasminogen is converted to plasmin via two primary serine proteases, tissue
plasminogen activator (tPA), and urokinase plasminogen
activator (uPA). Plasmin acts as the primary brinolysin for
thrombus breakdown. tPA is synthesized and released by
endothelial cells and is found intravascularly [122, 123].
When compared to tPA, uPA has a lower afnity to plasminogen, is primarily extravascular, and is located in the urinary epithelium, macrophages, and monocytes [122]. In
vivo, both have very short half-lives of 4–8 min and are
hepatically cleared. This brief half-life is attributable to the
high concentrations of circulating serine protease inhibiting
factors like plasminogen activator-inhibitor-1(PAI-1). Serine
protease inhibitors play a pivotal role to inhibit excess and
unregulated plasmin activity. Our understanding and appreciation of brinolysis has been greatly improved with the
advent of rotational thromboelastography (ROTEM).
ROTEM allows for a visual representation of brinolysis and
can indicate normal, hyper, or hypoactive brin breakdown.
A detailed description of the many components of the brinolytic pathway is beyond the scope of this paper. A review
of the most common antibrinolytics is below.
Antibrinolytics act by inhibiting the brinolytic cascade and preventing the breakdown of blood clots. Their use
has been broadly studied for control of hemorrhage in
trauma, cardiac surgery, traumatic brain injury, and numerous other clinical situations. Examples of antibrinolytics
include aprotinin, tranexamic acid (TXA), and epsilon-aminocaproic acid. Aprotinin is a serine protease inhibitor that
is no longer used in clinical practice. Results from the blood
conservation using antibrinolytics in a randomized trial
(BART) found an increased risk of 30-day mortality after
use in cardiac surgery [123, 124]. Subsequent studies have
also shown that patients given aprotinin have an increased
risk of kidney failure, stroke, heart failure, and 5-year mortality [123–125]. As a result of these ndings, clinical focus
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has shifted to the lysine analogs, TXA, and epsilon-aminocaproic acid.
Both tranexamic acid (TXA) and epsilon-aminocaproic
acid are synthetic lysine analogs that work by competitively
inhibiting the activation of plasminogen to plasmin [125].
The inhibition of plasminogen maintains brin integrity and
prevents clot degradation. TXA is 6–10 times more potent
than its counterpart epsilon-aminocaproic acid [126]. Unlike
aprotinin, both lysine analogs have been shown to increase
thrombus formation by increasing ADP content in platelets
without resulting in increased thromboembolic events like a
pulmonary embolus [126]. TXA has also been found to have
anti-inammatory properties by mitigating cytokine release.
A randomized controlled trial consisting of 50 patients
undergoing cardiopulmonary bypass (CPB) found that
patients who received TXA had a signicantly lower levels
of inammatory markers compared to those that received
placebo [127]. Decreased levels of inammatory cytokines
translate to less severe vasoplegic shock, less time requiring
vasopressor support, and decreased time for mechanical
respiratory support in the postoperative period [127]. In
patients undergoing cardiac surgery with CPB, either TXA
or epsilon-aminocaproic acid is routinely given to reduce
perioperative bleeding and also subsequently decrease transfusion of blood products.
Lysine analogs have also shown signicant benets in
noncardiac surgery. A recent meta-analysis included over
10,000 patients and found that those who received TXA had
a 38% reduction in probability to require a blood transfusion
compared to those patients who did not receive TXA [128].
The landmark CRASH-2 study looked at TXA administration in over 20,000 hemorrhagic trauma patients [129].
Patients who received TXA upon initial presentation were
found to have a signicant reduction in all-cause mortality
and death due to bleeding compared to those that did not get
TXA [128]. Even more recently, the CRASH-3 trial looked
at TXA administration within 3h in patients with traumatic
brain injury [130]. Findings were signicant for a reduction
in injury-related death in those that received TXA compared
to those that did not [130]. Both TXA and epsilonaminocaproic acid have also been found to be benecial for
reducing blood loss in orthopedic surgery, facilitating control of gastrointestinal hemorrhage and pulmonary hemorrhage [126].
TXA and epsilon-aminocaproic acid have a half-life of
2–3h and are primarily cleared renally. Clinicians need to
be cognizant of potential adverse effects associated with
lysine analogs. High-dose TXA is associated with a dosedependent increase in seizures [131]. Epsilon-aminocaproic
acid may also have an increased risk of renal dysfunction;
however, more research needs to be done for
conrmation.
Antiplatelets
Antiplatelet drugs work by inhibiting the capacity of platelets to participate in the clotting process. There are several
discrete mechanisms by which platelets activate and aggregate. Thus, there are several pharmacologic targets. A growing area of concern and research are the various interactions
antiplatelet drugs can participate in with other drugs and
commonly consumed substances.
When vessel endothelium is damaged, platelets are
exposed to subendothelial matrix, which triggers multiple
intracellular signaling pathways that lead to glycoprotein
IIb/IIIa complexes on platelets activating and binding to
brinogen, which results in platelet aggregation. One of
these intracellular pathways is activated by thromboxane A2,
which is produced by activated of cyclooxygenase-1 [132].
The antiplatelet action of aspirin is primarily mediated
through its inhibition of COX-1 and consequently its inhibition of the thromboxane A2 pathway to platelet activation.
Aspirin is unique among the NSAIDs in that it irreversibly
inhibits COX by acetylating serine residues. It is readily
absorbed in the acidic gastric environment where it can
inhibit the protective effects of prostaglandins on the stomach lining [133]. Thromboxane A2 inhibition within platelets
is cumulative with repeated low doses of aspirin due to the
irreversible enzyme inactivation via acetylation throughout
the 7–10-day lifetime of platelets. This allows for aspirin to
be given once daily and be effective despite its very short
half-life (15–20min) [132]. For patients with ACS, a recommended 150–325 mg of oral aspirin is chewed to achieve
rapid inhibition of thromboxane A2 [134]. Frequently aspirin
is used for treatment and prophylaxis of pathologic thrombus
formation. 100mg/day is sufcient for prevention of thrombus formation in the coronary circulation; higher doses may
be required for the prevention of vascular events in the cerebral and peripheral circulation [13].
Aspirin has numerous interactions with various drugs.
While non-aspirin NSAIDs also inhibit COX, they are not
useful for platelet inhibition due to their reversible mode of
action, which does not ensure permanent platelet inhibition.
Most NSAIDs including, celecoxib, dipyrone (active metabolite), ibuprofen, ufenamic acid, naproxen, nimesulide,
oxaprozin, and piroxicam signicantly interfere with the
antiplatelet activity of aspirin. Diclofenac, ketorolac, and
acetaminophen do not interfere with aspirin. This is thought
to be due to interfering with NSAIDs forming hydrogen
bonds with the aspirin binding site [135]. There is also evidence that co-administration can lead to anincreased risk of
myocardial infarction [81]. Alcohol consumption with aspirin is associated with anincreased risk of GI bleeding [136],
and smoking cigarettes increases platelet aggregation and
suppressing the effect of aspirin [137]. When administered
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with tamoxifen, aspirin decreases the angiogenic potential
of some breast cancers [138]. There is evidence which
shows that aspirin can blunt the effect with ACE-inhibitors,
but paradoxically, there is evidence of reduced mortality
with co-administration [139]. Triple therapy with ACEinhibitors, diuretics, and NSAIDs, including aspirin, has
been associated with anincreased risk of acute kidney injury
[140]. Serotonergic agents, such as selective serotonin reuptake inhibitors, can increase risk of bleeding when combined with any oral anticoagulant, including antiplatelets
and aspirin [141].
P2Y12 is an adenosine diphosphate (ADP) receptor that,
once activated, propagates intracellular signals that increase
intracellular calcium, alter platelet shape, and increase platelet aggregation [142]. P2Y12 antagonists block these receptors. The use of aspirin and a P2Y12 receptor antagonist,
known as dual antiplatelet therapy, is the basis of treatment
in patients with ACS and those undergoing coronary stenting
[132]. Clopidogrel and prasugrel are both prodrugs that need
biotransformation in the liver to become active [143]. These
two drugs irreversibly inhibit the P2Y12 receptor. Steadystate inhibition of platelet function is noted after 5–7days of
clopidogrel maintenance dosing, accounting for the role of a
loading dose to achieve more rapid inhibition. For clopidogrel, the recommended loading dose is 600 mg, and maintenance dose is 75mg [132].
Clopidogrel is the most popular P2Y12 inhibitor and has
numerous interactions with other substances. Proton-pump
inhibitors (PPIs), such as omeprazole and esomeprazole
(both substrates and inhibitors of CYP2C19), are associated
with decreased inhibition of platelet aggregation by clopidogrel [144, 145]. However, more research remains on whether
this affects clinical outcomes. Unlike aspirin, nicotine was
found to increase the antiplatelet activity of clopidogrel
[146], while grapefruit juice and ketoconazole decrease antiplatelet activity [147] due to the induction and inhibition of
liver cytochrome enzymes respectively. Clopidogrel, aspirin,
and warfarin have increased risk of GI bleeding when taken
in combination than when any is taken alone [148].
Ticagrelor, another P2Y12 inhibitor, acts by reversibly
binding P2Y12 away from the active site [132]. Ticagrelor is
not a prodrug, and the recommended loading and maintenance doses are 180mg once and 90mg twice per day [132].
Ticagrelor is more effective than clopidogrel in preventing
major cardiovascular events in patients with acute coronary
syndromes, but is associated with increased bleeding events,
ventricular pauses, and dyspnea [142]. Some research has
shown evidence that administration of high doses of aspirin
can blunt ticagrelor’s effects [142, 149]. Ticagrelor is an
inhibitor of CYP3A4 and consequently can increase plasma
concentrations of simvastatin and lovastatin. This could
potentially catalyze rhabdomyolysis and myopathy in vulnerable patients [150]. Statins and ticagrelor are commonly
co-administered for long-term maintenance of ACS patients,
and more research needs to be conducted to stratify risk and
monitor long-term patient outcomes.
The intracellular signals generated by the stimulation of
platelet receptors results in conformational change of the
major platelet adhesion receptor, GPIIb/IIIa (integrin-α
IIbβ3
)
[151]. GPIIb/IIIa exists in a low-afnity conformation on the
resting platelet, which can bind immobilized, but not soluble, brinogen. When platelets are activated, signals are
propagated from within the platelet, which leads to a change
in the conformation of GPIIb/IIIa from a low-afnity to a
high-afnity state that enables binding to soluble plasma
proteins. These protein ligands include vWF, bronectin,
and the primary GPIIb/IIIa ligand brinogen [151, 152].
Thus, this integrin receptor is the crux of stable platelet
aggregation and thrombus formation, making it an excellent
target for pharmacotherapy.
GPIIb/IIIa inhibitors prevent brinogen from binding to
activated platelets, thus directly inhibiting their aggregation.
Three agents are currently in use: abciximab, a humanized
antigen-binding fragment of a mouse monoclonal antibody;
eptibatide, a cyclic heptapeptide with a motif mimicking
the brinogen binding sequence within GPIIb/IIIa; and tiroban, a nonpeptidic small molecule also mimicking the
brinogen binding site [153]. However, except in high-risk
patients, the clinical use of integrin αIIbβ3 antagonists has
recently decreased due to the increased use of ADP receptor
antagonists. This replacement stems from the demonstrated
benet of ADP receptor antagonists [154]. Therefore, the
clinical benet derived from GPIIb/IIIa inhibitors seems to
be restricted to particular high-risk subgroups, such as
patients with MI undergoing PCI without pretreatment with
a P2Y12 antagonist [152]. GPIIb/IIIa inhibitors are potent
antithrombotic drugs and can cause bleeding complications
in up to 50% of patients [155].
There are other less well-known and less studied drugs
that affect platelet function. Cilostazol inhibits phosphodiesterase III and increases levels of cyclic AMP, which leads to
vasodilation, reduction of vascular smooth muscle proliferation, and inhibition of platelet aggregation. Cilostazol is suggested for symptomatic management of peripheral vascular
disease and has been used after percutaneous coronary intervention and for secondary prevention of non-cardioembolic
stroke or TIA.Its effects are strongly potentiated by ketoconazole and likely by other CYP3A4 inhibitors such as itraconazole, uconazole, miconazole, uvoxamine, uoxetine,
nefazodone, sertraline, and macrolides [156]. There is evidence that it is moderately inhibited by lovastatin [156].
Dipyridamole blocks the uptake of adenosine, which acts
on the platelet A
-receptor to activate platelet adenylate
2
cyclase, reducing platelet aggregation. Dipyridamole also
inhibits phosphodiesterase. This drug is used for prevention
of postoperative thromboembolic complications associated
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