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