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Cardiovascular drugs: some important
interaction
Prof. Dr Prof. Dr Milica ProstranMilica Prostran
Department of Pharmacology, Clinical Pharmacology andDepartment of Pharmacology, Clinical Pharmacology and
Toxicology School of Medicine, University of BelgradeToxicology School of Medicine, University of Belgrade
Belgrade, SerbiaBelgrade, Serbia
Should be able to answerShould be able to answer
•• DDefine drug interactionefine drug interactionss
•• DDescribe a mechanism of interactionsescribe a mechanism of interactions
•• Metabolic interactions (Metabolic interactions (inducers and inhibitorsinducers and inhibitors))
•• HHow to avoid or manage metabolic interactionsow to avoid or manage metabolic interactions•• HHow to avoid or manage metabolic interactionsow to avoid or manage metabolic interactions
•• HHigh risk patients and drugsigh risk patients and drugs
•• GGeneral strategies for the management of eneral strategies for the management of interactioninteractionss
Magyar, 2003Magyar, 2003
Definition
Drug interaction can be defined as the modification of
the effects of one drug (object drug) by the prior or the effects of one drug (object drug) by the prior or concomitant administration of another drug
(precipitant drug)
The clinical result of a drug−drug
interaction may manifest as:
• Antagonism (ie. 1 + 1 < 2)• Antagonism (ie. 1 + 1 < 2)
• Synergism (ie. 1 + 1 > 2)
• Idiosyncratic (ie. a response unexpected from the known effects of either drug)
• Simple additive or antagonistic effects anticipated to occur based on known pharmacological activity are not necessarily included:
• The additive blood pressure lowering effects of combining two antihypertensive agents
• Obvious antagonistic effects of beta blockers and isoproterenol
•• Predictability of drug interactions:Predictability of drug interactions:
oo Whether the interaction occurs and produces an Whether the interaction occurs and produces an
adverse effect or not depends on:adverse effect or not depends on:
�� The presence or absence of factors that The presence or absence of factors that
predispose to the adverse effects of drug predispose to the adverse effects of drug
interactions such as diseases, organ function, dose interactions such as diseases, organ function, dose interactions such as diseases, organ function, dose interactions such as diseases, organ function, dose
of drugs, etc.of drugs, etc.
��Awareness on the part of the prescriber, so that Awareness on the part of the prescriber, so that
appropriate monitoring can be ordered or appropriate monitoring can be ordered or
preventive measures takenpreventive measures taken
Horn, 2007
•• Clinically documented interactions:Clinically documented interactions:
oo Clarithromycin:Clarithromycin: ↓ statin metabolis↓ statin metabolis [[PredictablePredictable]:]:
�� Interaction occurs in most patients receiving the Interaction occurs in most patients receiving the combinationcombination
oo Clofibrate:Clofibrate: ↑ risk of myopathy↑ risk of myopathy [[Non predictableNon predictable]:]:oo Clofibrate:Clofibrate: ↑ risk of myopathy↑ risk of myopathy [[Non predictableNon predictable]:]:
�� Interaction occurs only in some patients receiving the Interaction occurs only in some patients receiving the combinationcombination
oo Diltiazem:Diltiazem: ↓ statin metabolism↓ statin metabolism [[Non establishedNon established]:]:
�� Insufficient data available on which to base estimate of Insufficient data available on which to base estimate of predictabilitypredictability
• A primary concern is the clinical relevance or
significance of the interaction
• The primary factors that define clinical
significance include:
• SIGNIFICANCE RATING• SIGNIFICANCE RATING
• The time of ONSET of the effects of the interaction
• The potential SEVERITY of the interaction
• The DOCUMENTATION that the interaction occurs
clinically
SIGNIFICANCE RATING
Anticoagulants (eg. warfarin) and NSAIDsAnticoagulants (eg. warfarin) and NSAIDs
• Significance:
• 1, 2, 3, 4, 5
• Onset:• Rapid
• Delayed
• Severity:• Severity:• Major
• Moderate
• Minor
• Documentation:• Established
• Probable
• Suspected
• Possible
• Unlikely
SIGNIFICANCE RATING
Anticoagulants (eg. warfarin) and NSAIDsAnticoagulants (eg. warfarin) and NSAIDs
• Effects:• Anticoagulant activity may be increased by NSAIDs, increasing risk of bleeding
• Mechanism:• Gastric irritation and decreased platelet function contribute
• Management:• Management:• Monitor patients closely and instruct them to report signs and symptoms of bleeding to health care provider
• Note:• Warfarin may be subject to many (up to 80) drug interactions
• Two major known sites of interaction are:• The plasma proteins where warfarin is bound while circulating• The hepatic cytochrome P450 system were warfarin is broken down by CYP2C9
Tatro et al., 2004
•• Direct thrombin inhibitor dabigatran etexilate:Direct thrombin inhibitor dabigatran etexilate:
oo Dabigatran etexilate and dabigatran are not Dabigatran etexilate and dabigatran are not
metabolised by cytochrome P450 system and have metabolised by cytochrome P450 system and have
no no in vitroin vitro effects on human cytochrome P450 effects on human cytochrome P450
enzymesenzymesenzymesenzymes
oo Dabigatran etexilate + diclofenac:Dabigatran etexilate + diclofenac:
�� The plasma exposure of both drugs remainThe plasma exposure of both drugs remainss unchanged unchanged
indicating a lack of PK interactionsindicating a lack of PK interactions
�� Due to the risk of haemorrhage, notabDue to the risk of haemorrhage, notablly with NSAIDs y with NSAIDs
with twith t1/21/2 > 12 hours, close observation for signs of > 12 hours, close observation for signs of
bleeding is recommendedbleeding is recommended
•• Transporter interactions:Transporter interactions:
oo Dabigatran etexilate is a substrate of the efflux transporter PDabigatran etexilate is a substrate of the efflux transporter P--
glycoproteinglycoprotein
oo Amiodarone is an inhibitor of this transporterAmiodarone is an inhibitor of this transporter
oo Amiodarone + dabigatran etexilate:Amiodarone + dabigatran etexilate:
oo The extent and rate of absorption of amidarone is unchangedThe extent and rate of absorption of amidarone is unchangedoo The extent and rate of absorption of amidarone is unchangedThe extent and rate of absorption of amidarone is unchanged
oo Dabigatran AUC and CDabigatran AUC and Cmaxmax are increased by 60% and 50%, respectivelyare increased by 60% and 50%, respectively
oo Mechanism of this interaction is not completely clarifiedMechanism of this interaction is not completely clarified
oo IInn view of the long tview of the long t1/21/2 of amiodarone, the potential for the of amiodarone, the potential for the
interaction may exists for weeks after discontinuation of interaction may exists for weeks after discontinuation of
amiodaroneamiodarone
oo Dosing of dabigatran etexilate should be reduced to 150 mg dailyDosing of dabigatran etexilate should be reduced to 150 mg daily
•• Transporter inhibitors:Transporter inhibitors:
oo ClarithromycinClarithromycin
oo VerapamilVerapamil
oo QuinidineQuinidine--contraindicatedcontraindicated
•• Caution should be exercisedCaution should be exercised
•• Transporter inducTransporter inducersers::
oo St John’ wort (St John’ wort (Hypericum perforatumHypericum perforatum))
oo RifampicinRifampicin
•• May reduce the systemic exposure to dabigatranMay reduce the systemic exposure to dabigatran
CYTOCHROME P450CYTOCHROME P450
Cytochome P450 izoenzyme Inducing drugs
CYP1A2 • Barbiturates
• Omeprazole
• Phenytoin
• Tobacco smoke
CYP2D6 • ?
Drugs that induce cytochrome P450 izoenzymes
CYP2C9 • Barbiturates
• Rifampicin (rifampin)
CYP2C19 • ?
CYP3A4 • Barbiturates
• Carbamazepine
• Dexamethasone
• Rifampicin
Enzyme inductionEnzyme induction
•• IIncreased production of drug metabolising enzymes ncreased production of drug metabolising enzymes (primarily Phase I metabolism)(primarily Phase I metabolism)
•• FFor maximum effect or maximum effect 2 to 2 to 3 weeks may be required3 weeks may be required
•• SSome drugs (carbamazepine) may increase ome drugs (carbamazepine) may increase its its own own metabolismmetabolism
•• IIt is a reversible process (slower process than int is a reversible process (slower process than inductionduction))•• IIt is a reversible process (slower process than int is a reversible process (slower process than inductionduction))
•• CCharacteristics: slow onset haracteristics: slow onset
DDecreases the therapeutic activity of the object drugecreases the therapeutic activity of the object drug
IIf precipitant drug discontinuedf precipitant drug discontinued,, toxicity could occurtoxicity could occur
Examples: phenytoin + mexiletineExamples: phenytoin + mexiletine
Magyar, 2003Magyar, 2003
Cytochome P450 izoenzyme Inhibiting drugs
CYP1A2 • Enoxacin
• Cimetidine
• Fluvoxamine
• Grapefruit juice:
• Bioflavonoid naringenin
• Furanocoumarin
Drugs that inhibit cytochrome P450 izoenzymes
• Furanocoumarin
dihydrobergamottin
CYP2D6 • Fluoxetine
• Quinidine
• Ritonavir
CYP2C9 • Fluconasole
• Fluoxetine
Cytochome P450 izoenzyme Inhibiting drugs
CYP2C19 • Fluoxetine
• Omeprazole
CYP3A4 • Cimetidine
• Erythromycin
Drugs that inhibit cytochrome P450 izoenzymes
• Erythromycin
• Grapefruit juice
• Ketoconazole
• Ritonavir
Enzyme inhibitionEnzyme inhibition
•• TThe most common mechanism of drug interactionhe most common mechanism of drug interaction
•• CCompetition occurs between the precipitant ompetition occurs between the precipitant and and object drug on object drug on the active site of the enzyme the active site of the enzyme
•• OOnset of interaction is rapid, occurring within hoursnset of interaction is rapid, occurring within hours
•• NNon competitive mechanisms are existing less commonly on competitive mechanisms are existing less commonly
•• TThe enzyme inhibition is dose relatedhe enzyme inhibition is dose related
•• RReversal of interaction occurs usually within 24 hourseversal of interaction occurs usually within 24 hours•• RReversal of interaction occurs usually within 24 hourseversal of interaction occurs usually within 24 hours
•• IIncreases plasma concentrations of the object drugncreases plasma concentrations of the object drug
•• TThe pharmacological and the adverse effects are potentiatehe pharmacological and the adverse effects are potentiatedd
Examples: erythromycin + antihistamines Examples: erythromycin + antihistamines
omeprazol + diazepamomeprazol + diazepamMagyar, 2003Magyar, 2003
•• HMGHMG--CoA reductase inhibitors are susceptible CoA reductase inhibitors are susceptible to CYP3A4 inhibitors/CYP3A4 inductorsto CYP3A4 inhibitors/CYP3A4 inductors
oo LovastatinLovastatin
oo SimvastatinSimvastatinoo SimvastatinSimvastatin
oo Atorvastatin (to a lesser extent)Atorvastatin (to a lesser extent)
•• Increased risk of additive myopathy with other Increased risk of additive myopathy with other drugs that can cause myopathydrugs that can cause myopathy
Drug(s) affected
by NSAIDs
NSAID(s)
implicated
Effect(s) Management
Oral
anticoagulants
Azapropazone
Oxyphenazone
Phenylbutazone
Inhibition of metabolism of S-warfarin, increasing anticoagulant effect
• Avoid NSAIDs if
possible
• Careful
monitoring when
unavoidable
Digoxin All NSAIDs Potential reduction • Avoid
Pharmacokinetic drug interactions with NSAIDs
Digoxin All NSAIDs Potential reduction
in renal function
(particularly in very
young and very old):
• Digoxin CL ↓
• Plasma
concentration ↑
• Toxicity ↑
• Avoid NSAIDs if possible
• Frequent check of serum digoxin concentrations and serum creatinine
Drug affected by
NSAIDs
NSAID(s)
implicated
Effect(s) Management
Anticoagulants All
NSAIDs
• GIT mucosal damage
• Inhibition of plateletaggregation
• Risk of GIT bleeding
• Avoid NSAIDs if
possible
Pharmacodynamic drug interactions with NSAIDs
All diuretics:
loop and
thiazide
All
NSAIDs
• Risk of hemodynamic renal
insufficiency ↑
• Antihypertensive
effect ↓
• Avoid combination if possible
• Adjust diuretic dose or add another agent
NSAIDs + Aspirin or NSAIDs
•• Aspirin is reported to increase, decrease or have Aspirin is reported to increase, decrease or have no effect on serum indomethacin levelsno effect on serum indomethacin levels
•• It does not reduce serum levels of piroxicam and It does not reduce serum levels of piroxicam and sudoxicamsudoxicamsudoxicamsudoxicam
•• Aspirin reduces serum diclofenac, fenoprofen, Aspirin reduces serum diclofenac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, flurbiprofen, ibuprofen, ketoprofen, naproxen, pirprofen, tenoxicam and tolmetin levelspirprofen, tenoxicam and tolmetin levels
Other interactions with aspirin (Other interactions with aspirin (Fox et al., 2009Fox et al., 2009):):
•• Concurrent warfarin and aspirin therapy increases the Concurrent warfarin and aspirin therapy increases the
risk of bleeding, especially if aspirin doses are highrisk of bleeding, especially if aspirin doses are high
•• Aspirin inhibits COXAspirin inhibits COX--1 activity about 170 times more 1 activity about 170 times more
than COXthan COX--2:2:than COXthan COX--2:2:
oo Interaction with COXInteraction with COX--2 inhibitors is unlikely2 inhibitors is unlikely
NSAIDs with dominant COXNSAIDs with dominant COX--1 activity (ibuprofen, 1 activity (ibuprofen,
naproxen) interfere with cardioprotective activity of naproxen) interfere with cardioprotective activity of
aspirinaspirin
oo NSAIDs with dominant COXNSAIDs with dominant COX--2 activity (diclofenac) 2 activity (diclofenac)
do not interfere with cardioprotective activity of do not interfere with cardioprotective activity of
aspirinaspirin
•• Concomitant administration of ibuprofen (400 Concomitant administration of ibuprofen (400 mg/day) or 3 times per day but not rofecoxib, mg/day) or 3 times per day but not rofecoxib, acetaminofen, or diclofenac competitively acetaminofen, or diclofenac competitively antagonized the irreversible platelet inhibition antagonized the irreversible platelet inhibition antagonized the irreversible platelet inhibition antagonized the irreversible platelet inhibition induced by aspirin 81 mg/day in a randomized, induced by aspirin 81 mg/day in a randomized,
crossover study crossover study ((CatellaCatella−−LawsonLawson etet al., 2001al., 2001))
N Engl J Med, Vol. 345, 2001
http:/http:///circoutcomes.ahajournals.org/cgi/content/full/2/3/155circoutcomes.ahajournals.org/cgi/content/full/2/3/155
Conclusions:
•• "In patients recently hospitalized for serious coronary "In patients recently hospitalized for serious coronary
heart disease, naproxen had better cardiovascular safety heart disease, naproxen had better cardiovascular safety
than did diclofenac, ibuprofen, and higher doses of than did diclofenac, ibuprofen, and higher doses of
celecoxib and rofecoxib."celecoxib and rofecoxib."
http://www.jclinpharm.org/cgi/content/abstract/48/1/117http://www.jclinpharm.org/cgi/content/abstract/48/1/117
Aspirin + ACE inhibitors:Aspirin + ACE inhibitors:
•• ACE inhibitors and aspirin have potentially opposing ACE inhibitors and aspirin have potentially opposing
effects on renal hemodynamics:effects on renal hemodynamics:
oo Aspirin inhibits the formation of vasodilatory prostaglandinsAspirin inhibits the formation of vasodilatory prostaglandins
oo ACE inhibitors promote the formation of vasodilatory ACE inhibitors promote the formation of vasodilatory
prostaglandinsprostaglandins
•• When ACE inhibitors are chronically used for heart When ACE inhibitors are chronically used for heart
failure, postinfarct protection and highfailure, postinfarct protection and high--risk prevention, risk prevention,
they are still beneficial when aspirin is addedthey are still beneficial when aspirin is added
•• Aspirin did reduce but not eliminate the ACE Aspirin did reduce but not eliminate the ACE
inhibitor’s beneficial effect on major clinical events:inhibitor’s beneficial effect on major clinical events:
oo A practical policy is to keep the aspirin dose low, especially in A practical policy is to keep the aspirin dose low, especially in
those with hemodynamic problems such as heart failurethose with hemodynamic problems such as heart failure
The risk of aspirinThe risk of aspirin--induced GI induced GI
bleeding is increased by:bleeding is increased by:
•• AlcoholAlcohol
•• CorticosteroidsCorticosteroids
•• NSAIDsNSAIDs
The efficacy of aspirin is decreased by:The efficacy of aspirin is decreased by:
•• PhenobarbitalPhenobarbital
•• PhenitoinPhenitoin•• PhenitoinPhenitoin
•• RifampicinRifampicin
Aspirin increases the effect of:Aspirin increases the effect of:
•• Oral hypoglycaemic agentsOral hypoglycaemic agents•• Oral hypoglycaemic agentsOral hypoglycaemic agents
•• InsulinInsulin
Aspirin may reduce the efficacy ofAspirin may reduce the efficacy of::
•• Uricosuric drugs such as sulfinpyrazoneUricosuric drugs such as sulfinpyrazone
•• ProbenecidProbenecid•• ProbenecidProbenecid
•• Combination with thiazide diuretics retards Combination with thiazide diuretics retards the urinary excretion of uric acid, increasing the urinary excretion of uric acid, increasing the risk of goutthe risk of gout
Facts on NSAIDs interactions
•• The elderly and patients with diabetes, renal or The elderly and patients with diabetes, renal or
cardiovascular disease are most at risk from drug cardiovascular disease are most at risk from drug
interactions with NSAIDsinteractions with NSAIDs
•• The most important interactions of NSAIDs are The most important interactions of NSAIDs are
pharmacodynamicpharmacodynamicpharmacodynamicpharmacodynamic
•• There are also some important pharmacokinetic There are also some important pharmacokinetic
interactions involving NSAIDs, but:interactions involving NSAIDs, but:
•• NSAIDs generally have little effect on hepatic clearance of NSAIDs generally have little effect on hepatic clearance of
other drugsother drugs
•• Pyrazole NSAIDs: phenylbutazone and azapropazone inhibit Pyrazole NSAIDs: phenylbutazone and azapropazone inhibit
the metabolism of warfarin, tolbutamide and phenytointhe metabolism of warfarin, tolbutamide and phenytoin
•• COXCOX--2 inhibitors (coxibs):2 inhibitors (coxibs):•• CelecoxibCelecoxib
•• ParecoxibParecoxib
•• RofecoxibRofecoxib
•• ValdecoxibValdecoxib
•• Like nonselective NSAIDs, coxibs are Like nonselective NSAIDs, coxibs are hepatically metabolized:hepatically metabolized:hepatically metabolized:hepatically metabolized:•• Rofecoxib primarily by reduction by cytosolic Rofecoxib primarily by reduction by cytosolic enzymesenzymes
•• Celecoxib by P450 enzyme system: CYP2C9Celecoxib by P450 enzyme system: CYP2C9
•• Celecoxib inhibits CYP2D6 and may affect Celecoxib inhibits CYP2D6 and may affect concentrations of CYP2D6 substratesconcentrations of CYP2D6 substrates
• The best strategy for treating pts with both arthritis and risk for cardiovascular events would be to first try acetaminophen, up to 4 g/day
• If acetaminophen is not successful, than naproxen may be prescribed
•• If the patient is at increased risk for gastrointestinal event caused by aspirin or naproxen (eg. age > 60 years, history of ulcers, etc.), then a gastroprotective agent can be added (a proton pump inhibitor or misoprostol)
•• NSAIDs are among the most widely used classes of NSAIDs are among the most widely used classes of drugs worldwide, available both trough prescription and drugs worldwide, available both trough prescription and over the counter (OTC)over the counter (OTC)
•• NSAIDs are prescribed for a wide variety of indicationsNSAIDs are prescribed for a wide variety of indications
•• They are frequently taken by patients who are taking They are frequently taken by patients who are taking other drugs, especially the elderly who are likely to have other drugs, especially the elderly who are likely to have comorbid diseasescomorbid diseasescomorbid diseasescomorbid diseases
•• Approximately 20% of patients taking NSAIDs will Approximately 20% of patients taking NSAIDs will develop 1 or > 1 of a variety of renal function develop 1 or > 1 of a variety of renal function abnormalitiesabnormalities
•• Potential drug interactions are identified in more than Potential drug interactions are identified in more than 50% of all patients treated with NSAIDs for symptoms 50% of all patients treated with NSAIDs for symptoms of arthritis aloneof arthritis alone
And something more…And something more…
Drug Herb Possible effects Clinical tips
AspirinAspirin •• ChamomileChamomile
•• GarlicGarlic
•• ParsleyParsley
•• Ginkgo bilobaGinkgo biloba
•• May ↑ risk of May ↑ risk of
bleeding because ofbleeding because of
coumarin or coumarin or coumarin coumarin derivatives in herbderivatives in herb
•• Herb may ↓ platelet Herb may ↓ platelet
•• Monitor pts forMonitor pts for
signs and signs and
symptoms of symptoms of
increased increased
bleedingbleeding
•• Monitor resultsMonitor results
Some herb-drug interactions I
activation factoractivation factor
•• May ↑ bleeding May ↑ bleeding
time in susceptible time in susceptible ptspts
•• Monitor resultsMonitor results
of hematologicalof hematological
and coagulationand coagulation
studiesstudies
•• Advise pts to Advise pts to
consult healthconsult health
care providercare provider
before using herbbefore using herb
Drug Herb Possible effects Clinical tips
AtenololAtenolol •• GingerGinger •• May antagoniseMay antagonise
effect of drugeffect of drug
•• Monitor BPMonitor BP
CaptoprilCaptopril •• CapsaicinCapsaicin •• May ↑ risk of May ↑ risk of •• Discourage useDiscourage use
Some herb-drug interactions II
CaptoprilCaptopril •• CapsaicinCapsaicin •• May ↑ risk of May ↑ risk of
coughcough
•• Discourage useDiscourage use
•• GingerGinger •• May antagoniseMay antagonise
effect of drugeffect of drug
•• Monitor BPMonitor BP
Drug Herb Possible effects Clinical tips
DigoxinDigoxin •• St. John’ wort St. John’ wort •• May ↓ digoxin May ↓ digoxin
level level
•• Therapeutic Therapeutic
effect ↓effect ↓
•• Advise pts of Advise pts of
this effectthis effect
•• Monitor serumMonitor serum
levellevel
EnalaprilEnalapril •• St. John’ wort St. John’ wort •• May ↑ May ↑
photosensitivity photosensitivity
•• Advise pts toAdvise pts to
wear sunscreenwear sunscreen
Some herb-drug interactions III
EnalaprilEnalaprilphotosensitivity photosensitivity
adding to the riskadding to the risk
of sunburn or of sunburn or
skin rashskin rash
wear sunscreenwear sunscreen
or protectiveor protective
clothing duringclothing during
sun exposuresun exposure
FosinoprilFosinopril •• St. John’ wort St. John’ wort •• May ↑ May ↑
photosensitivity photosensitivity
adding to the riskadding to the risk
of sunburn or of sunburn or
skin rashskin rash
•• Advise pts toAdvise pts to
wear sunscreenwear sunscreen
or protective or protective
clothing duringclothing during
sun exposuresun exposure