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Major drug interactions 

Major drug interactions
Chapter:
Major drug interactions
Author(s):

Maja Hellfritzsch Poulsen

, and Marlene Lunddal Krogh

DOI:
10.1093/med/9780198759935.003.0023
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date: 17 October 2019

Introduction

A common definition of interactions is when the effects of one drug are changed by the presence of another drug, food, herbal medicine, or other exogenic substances. As a consequence, interactions can cause both an enhanced or a reduced effect of a drug, but also, just as importantly, a decreased or an increased risk of side effects, and thereby an increased risk of toxicity. We most commonly refer to interactions as being unwanted and unsought, but we must also remember that some interactions are used intentionally to obtain a more effective treatment such as combining antihypertensive drugs in order to reach the target BP.

Many drug–drug interactions (DDIs) are mainly theoretical and have never been proved to cause harm to patients, but some are potentially harmful and it is some of the latter that we will focus on in this chapter. The CV drugs that we have chosen to focus on are mainly those with the highest risk of severe side effects and/or with a narrow therapeutic window leaving only little room for changes in plasma concentrations before patients may experience potentially harmful symptoms. Importantly, there is large patient variability concerning whether or not patients develop symptoms due to an interaction, and thereby making the interaction clinically relevant for the individual patient. This makes it difficult to predict what might happen when a patient is given two or more drugs that interact. Avoiding interactions is often not possible, but with some appropriate precautions, co-medication is often possible despite clinically relevant interactions. Much of the information gathered in this chapter has been retrieved from relevant international databases and online tools, including Micromedex and Drugs.com, as well as updated books such as Stockley’s Drug Interactions, tenth edition for references, along with a few chosen studies and relevant ESC guidelines.

Mechanisms of interactions

Based on the underlying mechanism, DDIs can be categorized into pharmacokinetic (PK) and pharmacodynamic (PD) DDIs. It may be too simple sometimes to blame an interaction on just one specific mechanism, as we know that some clinically important interactions are more complex. Nevertheless, for clarification purposes, most of the DDIs in this chapter will be explained by the most important mechanism.

In PK-related interactions, one drug causes changes in the absorption, distribution, metabolization, and/or excretion of another drug. Many of these interactions can be proven by changes in the plasma concentration of the affected drug. PD-related interactions are based upon the mechanism of action of the drug and the side effects. PK changes are often more predictable, whereas PD changes are often unpredictable, individual, and reflected by an augmented or a reduced effect and/or side effects.

Part of drug metabolism includes oxidation caused by CYP450 enzymes, which are mainly located in the liver and intestine. These enzymes are divided into families and subfamilies and are named with the prefix ‘CYP’, followed by an Arabic number and a numerical number for the specific enzyme. These enzymes differ according to their substrates and genetic characteristics, but all can be induced and inhibited. When one drug is metabolized by several CYP enzymes, the clinical effect depends on the capacity of all enzymes involved.

P-glycoprotein (P-gp) is one of the most important ATP-binding cassette transporters in humans and is responsible for the transport of some drugs and metabolites in several organs such as the intestine, liver, and kidney, as well as the brain where it serves as a part of the blood–brain barrier. In the intestine, P-gp actively transports drugs that are substrates back to the lumen, thereby inhibiting the absorption of the drug, probably as a protective mechanism against toxic xenobiotics. P-gp has some individual variations and, like CYP450 enzymes, can be inhibited or induced, which can therefore have consequences in terms of developing toxicity or treatment failure.

In addition to the influence of CYP enzymes and P-gp, the metabolism of drugs can be changed in other ways, e.g. by the blood flow in the liver and/or kidneys.

Some clinically important principles of PK interactions are shown in Table 7.1.1, along with some clinical examples. It is important to note that interactions caused by inhibition of CYP450 enzymes start within a few days and cease when the inhibiting drug is no longer present, whereas interactions due to enzyme induction usually develop over several days to weeks and may persist for a long time after the inducing drug has been withdrawn.

Table 7.1.1 Clinically important principles of pharmacokinetic drug interactions and clinically relevant examples

Mechanism

Commonest causes with clinical relevance

Clinical examples

Absorption

Induction and inhibition of drug transporter proteins such as P-gp

Increased absorption of digoxin due to inhibition of P-gp by clarithromycin

Chelation or complex formation

Activated charcoal inhibits the absorption of dabigatran

Distribution

Protein binding

Often only relevant to the interpretation of therapeutic drug monitoring

Metabolism

Inhibition of CYP450 enzymes

Increased plasma concentration of simvastatin due to inhibition of CYP3A4 by amiodarone, thereby increasing the risk for muscle symptoms

Induction of CYP450 enzymes

Reduced plasma concentration of ciclosporin by rifampicin, causing an increased risk of transplant rejection

Excretion

Changes in renal tubular excretion

Reduced excretion of digoxin due to spironolactone

Changes in renal blood flow

NSAIDs cause a rise in the plasma concentration of lithium

NSAID, non-steroidal anti-inflammatory drug; P-gp, P-glycoprotein.

Table 7.1.2 shows the most common inhibitors, inducers, and substrates of the most common CYP450 enzymes, as well as of P-gp. This list is not exhaustive but shows some of the relevant potentially interacting drugs. Concerning CYP1A2, in addition to drugs, smoking is also mentioned because tobacco smoke induces this enzyme and smoking cessation, as well as starting smoking just a few cigarettes, may cause important changes in the plasma concentrations of the enzyme substrates. This is important, since smoking cessation is highly warranted in cardiac patients.

Table 7.1.2 Examples of substrates, inhibitors, and inducers of the commonest CYP450 enzymes and P-gp, as well as genetic differences for some of the enzymes

CYP enzyme or transporter

Substrates

Inhibitors

Inducers

Characteristics

1A2

Clozapine, duloxetine, imipramine, olanzapine

Amiodarone, ciprofloxacin, fluvoxamine

Carbamazepine, efavirenz, rifampicin, smoking

Some genetic variation

2B6

Ketamine, methadone

Clopidogrel, voriconazole

Carbamazepine, phenytoin, rifampicin

2C9

Celecoxib, diclofenac, irbesartan, losartan, naproxen, valproate, warfarin

Amiodarone, fluconazole, metronidazole, miconazole, voriconazole,

Carbamazepine, dicloxacillin, efavirenz, rifampicin, St John’s wort

Approximately 4% are slow metabolizers

2C19

Amitriptyline, citalopram, clopidogrel, labetalol

Esomeprazole, fluoxetine, oral contraceptives

Carbamazepine, efavirenz, rifampicin, St John’s wort

Approximately 3% of Caucasians and 20% of Asiatics are slow metabolizers. There are several inactivating mutations in the gene coding for CYP2C19 and genotyping is possible

2D6

Aripiprazole, atenolol, carvedilol, codeine, duloxetine, flecainide, fluoxetine, metoprolol, paroxetine, propafenone, risperidone, tramadol, venlafaxine

Amiodarone, celecoxib, citalopram, duloxetine, fluoxetine, methadone, paroxetine, sertraline, terbinafine

Approximately 7–8% of Caucasians and 1–2% of Afro-Americans and Asiatics are slow metabolizers due to multiple inactivating mutations in the CYP2D6 gene. Approximately 1% are ultra-fast metabolizers. Genotyping of both fast and slow metabolizers is possible

3A4

Amlodipine, apixaban, atorvastatin, diltiazem, edoxaban, felodipine, rivaroxaban, sildenafil, simvastatin, tamoxifen, verapamil

Amiodarone, clarithromycin, erythromycin, grapefruit juice, itraconazole, ketoconazole, verapamil, voriconazole

Carbamazepine, efavirenz, phenobarbital, rifampicin, St John’s wort

Expressed in the liver and gut wall

P-gp

Atorvastatin, carvedilol, digoxin, diltiazem, losartan, morphine, simvastatin, verapamil

Amiodarone, clarithromycin, erythromycin, itraconazole, ketoconazole, voriconazole, verapamil

Carbamazepine, phenobarbital, rifampicin, St John’s wort

Close relationship with CYP3A4

This table is not exhaustive but shows examples. Drugs in boldface are strong and moderate inhibitors.

Challenges and consequences of polypharmacy

There is no agreed definition of polypharmacy, and suggestions of whether it means receiving three, five, or six different drugs or whether it means receiving the wrong drugs have not been established. What the exact definition might be does not matter that much; what matters is that the more drugs a patient is taking, the more complicated it can be to obtain an overview of all drugs and the potential interactions, especially when adding or removing drugs from the medication list.

These complex medication lists are often the reason for drug dosing errors, harmful interactions, and drug toxicity, which may lead to hospitalizations. Several studies have shown that 5–12% of all hospitalizations are caused by drugs and that just a few groups of drugs cause the majority of hospitalizations, namely anticoagulants, antiplatelets, NSAIDs, opioids, and antihypertensives, because of their side effects.1 In particular, concerning antithrombotics, the combination of antiplatelets and anticoagulants, or the combination of any of those with NSAIDs, carries a high risk of severe bleeding.

Some of the precautions that can be taken to avoid harmful interactions are the following:

  • Identification of high-risk drugs with a narrow therapeutic window and potentially severe side effects, e.g. anticoagulants, antiarrhythmic drugs, digoxin, and many antipsychotics.

  • Identification of those patients who are more fragile and susceptible to harmful side effects, including the elderly and also patients with impaired organ function, e.g. renal, liver, or mental impairment.

  • Considering closer drug monitoring, e.g. measurements of INR and plasma concentrations, as well as closer monitoring of safety, e.g. ECG and renal function.

  • Considering a dose reduction upfront.

  • Making regular medication reviews and discontinuing drugs that are no longer needed.

  • Remembering to provide the patient with thorough information on which symptoms they should be aware of, and also considering giving information to relatives and caregivers, as well as to your colleagues who are also taking the case of this patient.

Specific drugs with a high risk of clinically important interactions

Interactions affecting antiarrhythmic drugs

AADs are highly heterogenous but are often regarded as being high-risk drugs because of the risk of toxicity leading to severe ventricular arrhythmia. Both PK and PD interactions differ among these drugs. Concerning PD interactions, a major issue is the risk of QT interval prolongation, and thereby a risk of TdP, due to the combination of drugs that have the ability to prolong the QT interval. However, this risk may also arise due to PK interactions or due to side effects of other drugs causing metabolic disturbances. There is some consensus on not to combine drugs with a high risk of causing prolongation of the QT interval and to be cautious when combining drugs with a moderate risk. Some of the most commonly used AADs are discussed in more detail in the following sections.

Beta-adrenoceptor antagonists

At present, β‎-adrenoceptor antagonists are generally considered as almost ideal AADs because of their broad antiarrhythmic effect and good safety profile. PK interactions vary among these drugs (see Table 7.1.2), with the most lipophilic β‎-adrenoceptor antagonists primarily metabolized by CYP2D6. Hence, drugs that inhibit this enzyme, e.g. propafenone, the antifungal terbinafine when used systemically, antidepressants such as fluoxetine, paroxetine (strong inhibitors), duloxetine, and sertraline, and cimetidine (moderate inhibitors), increase the plasma concentration of these β‎-adrenoceptor antagonists. Verapamil inhibits the hepatic breakdown of lipophilic β‎-adrenoceptor antagonists, increasing their plasma concentration. The most water-soluble β‎-adrenoceptor antagonists (e.g. atenolol and sotalol) are mainly excreted by the kidneys and are therefore rarely subjected to DDIs. β‎-adrenoceptor antagonists have a broad therapeutic index, and most patients tolerate a rise in their plasma concentrations, with the exception of HF patients in whom slow and careful titration may be warranted. Concerning PD interactions, there is a risk of additive cardiac depressant effects, such as hypotension and bradycardia, when used in combination with other drugs with similar side effects. β‎-adrenoceptor antagonists inhibit the competitive binding of catecholamines to β‎-adrenoceptors, thereby potentially decreasing the effect of these drugs, but with some differences between the drugs. β‎1-selective drugs (e.g. atenolol and metoprolol) selectively block receptors in cardiac tissue, but at high dosages, they also affect β‎2 receptors. Non-selective drugs block receptors (β‎2) in the lung and blood vessels (e.g. propranolol and carvedilol—carvedilol also block α‎1 receptors).

Calcium channel antagonists

Verapamil and diltiazem are mainly metabolized by CYP3A4. Thus, drugs that inhibit CYP3A4, e.g. erythromycin, clarithromycin, most azole antifungals, and some antiviral agents, increase the plasma concentration of these calcium channel antagonists, and inducers, such as rifampicin, will decrease their plasma concentration (see Table 7.1.2). The main issue concerning interactions with verapamil is its ability to inhibit CYP3A4 and P-gp. Verapamil may nearly double plasma digoxin levels2 and increase the levels of dabigatran, quinidine, ciclosporin, simvastatin, atorvastatin, and lovastatin. Diltiazem interacts with the same drugs, but to a lesser extent. Verapamil and diltiazem inhibit the AVN, causing PD interactions with other drugs that also inhibit the AVN, e.g. β‎-adrenoceptor antagonists, digoxin, and amiodarone. Verapamil cause arteriolar dilatation and exerts a direct negative inotropic effect on the heart. The negative inotropic effect of combining verapamil and disopyramide is considerable.

Amiodarone

Amiodarone is also mainly metabolized by CYP3A4. Thus, certain protease inhibitors, ketoconazole, itraconazole, clarithromycin, and verapamil may decrease the metabolism and increase the serum concentrations of amiodarone. Furthermore, amiodarone is also a substrate for P-gp. Grapefruit juice, usually >200mL a day, inhibits P-gp in the intestinal mucosa and can increase the bioavailability of oral amiodarone, resulting in increased plasma levels and a risk of toxicity.3 Therefore, grapefruit juice should be avoided during treatment with oral amiodarone. Concomitant use of P450 enzyme inducers, e.g. rifampicin, may lead to decreased serum concentrations and loss of efficacy. Amiodarone inhibits several of the P450 enzymes (mainly CYP1A1/2, CYP3A4, CYP2C9, and CYP2D6), as well as P-gp. It thereby has the potential to increase the plasma levels of many of the enzyme substrates, e.g. metoprolol, some antidepressants, and some statins. The use of statins that are P450 substrates in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis, and this is why a maximum dose of 20mg of simvastatin should be considered when given in combination with amiodarone. In addition, digoxin plasma levels and the anticoagulant effect of warfarin are increased. Thus, the dose of digoxin, as well as that of warfarin, should be reduced, and plasma digoxin levels and INR should be monitored. Also, the effect of dabigatran and the other NOACs are increased. Concerning PD interactions, the main issue concerns the co-administration of amiodarone with drugs known to prolong the QT interval, e.g. some other AADs, some antipsychotics, some antidepressants, some fluoroquinolone and macrolide antibiotics, and some azole antifungals. In addition, concomitant use of drugs with depressant effects on the sinoatrial and atrioventricular nodes can potentiate the electrophysiological and haemodynamic effects of amiodarone, resulting in bradycardia, sinus arrest and AVB, and hypotension. Recently, severe bradycardia has been reported when combining amiodarone with the new direct-acting antiviral drugs used to treat chronic HCV infection—sofosbuvir and daclatasvir. Thus, either another AAD should be used or the heart rate should be monitored, especially during the first 48h. Due to the very long half-life of amiodarone of up to 100 days, in cases of maintenance treatment, the interactions may last several months after stopping amiodarone.

Digoxin

The main DDIs with digoxin are due either to P-gp or to the fact that digoxin is excreted by the kidneys. The clinically relevant PK interactions due to P-gp2 are related to concomitant treatment with, for example, amiodarone, clarithromycin, verapamil, and other inhibitors of P-gp (see Table 7.1.2). In addition to P-gp inhibition, the interactions due to reduced renal excretion can also be due to drugs that reduce renal blood flow, e.g. NSAIDs, ACEIs, and spironolactone. Another type of interactions with digoxin is with drugs that, through inducing low levels of potassium, may increase the risk of toxicity. Such drugs include, for example, diuretics and amphotericin. None of these drugs are contraindicated, but attention should be paid to maintaining the potassium levels within the upper part of the normal range and, in cases of PK interactions, to monitor the side effects and, in some cases, serum digoxin levels.

Flecainide and propafenone

Flecainide is mainly metabolized by CYP2D6, and propafenone by several CYP enzymes. See Table 7.1.2 for drugs that inhibit or induce these enzymes. Both drugs may induce AVB, and potential PD interactions are with other drugs with the same profile. Careful observation of the QT and QRS intervals and for proarrhythmias should be considered.

Oral anticoagulants

Oral anticoagulants are widely used in the prophylaxis and treatment of thrombosis. Most anticoagulant users are elderly persons with a high frequency of comorbid conditions and concomitant medications, making them particularly susceptible to DDIs. Due to the potency of oral anticoagulants, DDIs can have serious consequences, potentially leading to thrombosis, bleeding complications, hospitalizations, and death.

The PK DDIs vary between the individual oral anticoagulant drugs, whereas the PD DDIs are similar in all oral anticoagulants.

Warfarin

VKAs are especially prone to clinically significant DDIs due to their extensive liver metabolism and narrow therapeutic index.

The most potent of warfarin’s enantiomers (S-enantiomer) is metabolized by CYP2C9, and inhibition of CYP2C9 will result in decreased metabolism of warfarin, leading to an increased anticoagulant effect. Conversely, induction of CYP2C9 will result in increased metabolism and thereby a decreased anticoagulant effect.4 A list of drugs known to inhibit or induce CYP2C9 can be found in Table 7.1.2.

INR should be monitored closely when initiating, as well as stopping, therapy with drugs serving as inhibitors and inducers of CYP2C9 in warfarin-treated patients, and the warfarin dose may have to be adjusted. If short-term therapy with a strong CYP2C9 inducer or inhibitor is necessary, warfarin therapy should be paused and replaced by LMWH during the treatment course and reinitiated afterwards.

The markedly less potent R-enantiomer is metabolized by CYP3A4. While the metabolism of R-warfarin indeed can be affected by concomitant therapy with inhibitors or inducers of CYP3A4, this will rarely lead to clinically significant changes in the anticoagulant activity of warfarin due to the low potency of R-warfarin.4

The list of drugs reported to potentially interact with warfarin is long. While some of the drugs on the list involve an interference with warfarin metabolism through the CYP system, other apparent DDIs more likely reflect an interaction between warfarin and the condition being treated or the side effects to the drug (e.g. dyspepsia leading to a change in food intake). Therefore, INR changes in relation to a change in drug therapy may be unpredictable despite detailed knowledge of the drug’s interference with the CYP system. For this reason, monitoring of INR should be considered in the context of any change in drug therapy.

Other vitamin K antagonists

Similar to warfarin, acenocoumarol is primarily metabolized by CYP2C9, and is therefore likely to interact with inhibitors and inducers of CYP2C9 (see Table 7.1.2).

CYP-dependent metabolism is less pronounced for phenprocoumon than for warfarin and acenocoumarol (60% versus 100%), making this pathway less important for the total elimination of phenprocoumon. Thus, the potential for CYP-mediated DDIs is lower for phenprocoumon than for warfarin and acenocoumarol. Further, the predominant CYP enzyme involved in phenprocoumon metabolism is CYP3A4 (the role of CYP2C9 is minor), and DDIs involving phenprocoumon will therefore more likely be caused by concomitant therapy with drugs interfering with the activity of CYP3A4 (see Table 7.1.2) than CYP2C9.

Non-vitamin K antagonist oral anticoagulants

An often mentioned benefit of NOACs, compared to VKAs, is the lower potential for DDIs. With a lower degree of liver metabolism and a wider therapeutic index, NOACs are indeed involved in fewer clinically relevant DDIs. However, while VKA dosing can be titrated ‘to fit’ the DDI, the options are limited in the context of NOACs due to their fixed dosing regimens. Concomitant treatment with a drug known or expected to interact significantly with NOACs will therefore lead to either a dose reduction or discontinuation of one of the agents (i.e. contraindicated combinations).

Importantly, NOACs are newly marketed drugs, and most of our knowledge concerning NOACs and DDIs is currently based on PK studies using differences in total drug exposure [i.e. area under the curve (AUC)] between NOAC users exposed to and those unexposed to the potentially interacting drug as a proxy for a DDI. The precise correlation between changes in the AUC and the effectiveness and safety of NOACs remains to be established. Studies focusing on the clinical significance of DDIs involving NOACs are very sparse.

PK DDIs involving NOACs are mediated through P-gp, for which all NOACs are substrates, and CYP3A4, which is responsible for liver metabolism of factor Xa inhibitors (especially rivaroxaban and apixaban).

The EHRA has proposed that potential DDIs involving NOACs can be categorized according to recommended handling: (1) do not combine (red in Fig. 7.1.1); (2) reduce the NOAC dose (orange in Fig. 7.1.1); (3) consider dose reduction if two drugs in this category are combined with the NOAC (yellow in Fig. 7.1.1); (4) no interventions or cautions are needed (white in Fig. 7.1.1); and (5) use with caution or avoid (pink in Fig. 7.1.1).5, 6 The categorization is based on available knowledge from drug labels and from PK and clinical DDI studies, and is intended for use in AF patients. The recommendations for specific combinations can be found in Fig. 7.1.1.

Fig. 7.1.1 Recommended clinical approach in the context of specific drug combinations involving NOACs. Red cells indicate contraindicated combinations. Orange cells indicate that the combination can be used, but the NOAC dose should be reduced. Yellow cells indicate that NOAC dose reduction should be considered when two or more ‘yellow drugs’ are used concomitantly with NOAC therapy. Pink cells indicate use with caution or avoid. White cells indicate that there is no need for intervention/caution, and grey cells indicate that no data on the combination are available.

Fig. 7.1.1 Recommended clinical approach in the context of specific drug combinations involving NOACs. Red cells indicate contraindicated combinations. Orange cells indicate that the combination can be used, but the NOAC dose should be reduced. Yellow cells indicate that NOAC dose reduction should be considered when two or more ‘yellow drugs’ are used concomitantly with NOAC therapy. Pink cells indicate use with caution or avoid. White cells indicate that there is no need for intervention/caution, and grey cells indicate that no data on the combination are available.

Source data from Heidbuchel H, Verhamme P, Alings M et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Eur Eur Pacing Arrhythm Card Electrophysiol J Work Groups Card Pacing Arrhythm Card Cell Electrophysiol Eur Soc Cardiol. October 2015;17(10):1467–507; and Steffel J, Verhamme P, Potpara TS et al. ESC Scientific Document Group. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39(16):1330–93.

Pharmacodynamic drug–drug interactions involving oral anticoagulants

Use of multiple antithrombotic drugs infers a synergistic effect on the bleeding risk. Use of more than one anticoagulant agent is contraindicated, even in the context of bridging. Combined use of an oral anticoagulant and one or more platelet inhibitor (e.g. clopidogrel and low-dose ASA) has the potential to increase the bleeding risk markedly and should only be used if absolutely indicated by guidelines.7

Other drugs known to increase the risk of bleeding in the context of oral anticoagulant therapy are NSAIDs (e.g. ibuprofen and high-dose ASA) and antidepressants mediating their action through interference with serotonin reuptake mechanisms [SSRIs, serotonin noradrenaline reuptake inhibitors (SNRIs), and clomipramine].

Statins

Statins (HMG CoA reductase inhibitors) are widely used in the prevention of CV disease. The risk of muscular side effects increases with increasing plasma levels of statins. Very high plasma levels can lead to rhabdomyolysis (muscular necrosis), which is a rare, but much feared, complication of statin therapy. Most cases of statin-associated rhabdomyolysis and myopathy are due to PK DDIs leading to the inhibition of hepatic metabolism of statins.

Concomitant treatment with simvastatin, lovastatin, or atorvastatin and a potent inhibitor of CYP3A4 (see Table 7.1.2) can result in up to a 5-fold increase in the AUC of the given statin.8 Such combinations should therefore be avoided. Short-term treatment with potent CYP3A4 inhibitors during therapy with simvastatin, lovastatin, or atorvastatin can be handled with a temporary interruption of statin therapy. In cases of long-term therapy with potent CYP3A4 inhibitors, statin therapy should be with a statin not dependent on CYP3A4 metabolism (e.g. rosuvastatin).

Simvastatin and lovastatin are more susceptible to CYP3A4 inhibition than atorvastatin, and even moderate CYP3A4 inhibition might lead to adverse muscular effects. Therefore, the dose of simvastatin and lovastatin should, in contrast to atorvastatin, be reduced when combined with moderate CYP3A4 inhibitors.

Liver metabolism of rosuvastatin through CYP2C9 is negligible. No clinically relevant DDIs between either rosuvastatin or fluvastatin and inhibitors of CYP2C9 have been described.

Other lipid-lowering drugs

There are no known DDIs involving either ezetimibe or any of the PCSK9 inhibitors (evolocumab and alirocumab).

Gemfibrozil serves as an inhibitor of CYP2C9, CYP2C19, and CYP1A2, as well as other metabolizing enzymes. It is contraindicated to use gemfibrozil in combination with dasabuvir and repaglinide. Further, when combined with statins (especially simvastatin), the risk of statin-related side effects is increased.8

Bile acid sequestrants, such as colestyramine, bind any kind of acids in the GI tract. These drugs therefore have the potential to decrease the absorption, and thereby the bioavailability, of several drugs (e.g. anticoagulants, digoxin, and thyroxine). Generally, intake of other drugs should be avoided from 1h before to 4h after the administration of a bile acid sequestrant.8

Proton pump inhibitors

PPIs inhibit the secretion of hydrochloric acid in the stomach by specific blockade of the proton pumps (the H+/K+-ATPase enzyme) of the parietal cells. PPIs may therefore reduce the absorption of active substances whose bioavailability is dependent on gastric pH (e.g. antifungal medication).

PPIs are almost exclusively metabolized primarily by CYP2C19 and, to a lesser extent, by CYP3A4. In addition to being a substrate, most PPIs also inhibit CYP2C19. Omeprazole and esomeprazole may elicit a more potent inhibition of CYP2C19.

Since the efficacy between PPIs is thought to be equal, the choice of a PPI with less CYP inhibition in case of a potential interaction is possible.

For potential PK interactions, see Table 7.1.2.

Since PPIs are essential in the prophylaxis of GI bleeding disorders in patients receiving antithrombotic treatment, co-administration with PPIs is often seen.

Data on the PK interaction between clopidogrel and PPIs have shown up to 45% reduction in exposure to the active metabolite of clopidogrel when administered concomitantly with omeprazole/esomeprazole. Although this PK interaction is mainly established for esomeprazole and omeprazole, it is not clear to what degree this also reduces the clinical efficacy of clopidogrel. The most plausible mechanism for the PK interaction is inhibition of CYP2C19 that converts clopidogrel to its active metabolite. This interaction can be overcome by switching to another PPI, such as pantoprazole or lansoprazole, or to a H2 receptor antagonist (except cimetidine). There have been concerns of a possible interaction with VKAs, but a recent observational study found no evidence of a clinically meaningful DDI.

ACE inhibitors and angiotensin II receptor blockers

The PD interaction potential is comparable for this group, despite minor differences in the mechanism of action.

ACEIs and ARBs both modulate the RAAS, and the overall effect is the same, causing vasodilatation that leads to a reduction in the BP without activating the sympathetic nervous system. Combining ACEIs/ARBs with other types of antihypertensive drugs (e.g. β‎-blockers, calcium channel antagonists) or vasodilators (e.g. nitrates) is considered safe but will be expected to act in synergy and potentiate the hypotensive effect of ACEIs and ARBs. A concern is the combined use with the renin inhibitor aliskiren, also acting on the RAAS and raising the risk of adverse events such as hypotension, hyperkalaemia, and decreased renal function (including acute renal failure). Dual blockade should only occur under specialist supervision, with close monitoring of BP, renal function, and potassium levels, and triple blockade with aliskiren and ACEIs/ARBs is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60mL/min/1.73m2) (see Fig. 7.1.2).

Fig. 7.1.2 Recommended clinical approach in the context of specific drug combinations involving ACEIs and ARBs. Red cells indicate contraindicated combinations. Orange cells indicate that the combination can be used, but the dose should be reduced. Yellow cells indicate that dose reduction should be considered.

Fig. 7.1.2 Recommended clinical approach in the context of specific drug combinations involving ACEIs and ARBs. Red cells indicate contraindicated combinations. Orange cells indicate that the combination can be used, but the dose should be reduced. Yellow cells indicate that dose reduction should be considered.

Source data from Heidbuchel H, Verhamme P, Alings M et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Eur Eur Pacing Arrhythm Card Electrophysiol J Work Groups Card Pacing Arrhythm Card Cell Electrophysiol Eur Soc Cardiol. October 2015;17(10):1467–507.

The risk of increased potassium levels is also with the concomitant use of potassium-sparing diuretics or potassium supplements and, in some cases, with the concurrent use of ACEIs and co-trimoxazole.

For NSAIDs, see Major drug interactions Analgesics, pp. [link][link].

A rarer interaction due to the same side effects is an increased risk of angio-oedema in patients taking both an ACEI and an mTOR inhibitor such as sirolimus.

Lithium

ACEIs/ARBs can raise lithium levels, with up to a 7-fold increase in the risk of lithium toxicity and an average rise in serum lithium levels of 35% (from 0.64 to 0.86mmol/L) and with a 26% decrease in lithium clearance after initiating treatment with an ACEI. The mechanism is not fully understood, but theories include inhibition of aldosterone activity, resulting in increased sodium loss by renal tubules and retention of lithium, as well as reduced thirst stimulation and fluid depletion caused by ACEIs. In cases of concomitant use of lithium with ACEIs or ARBs, consider reducing the initial lithium dose and monitoring lithium levels more frequently.

PK interactions differ between the two drug classes, but within the same class, the differences are minor. Despite these differences, PK interactions for both classes are comparably few and rarely clinically relevant. ACEIs are not known to be metabolized via the CYP enzyme system to a clinical relevant extent, and even though some ARBs (losartan, irbesartan, candesartan) are known to be metabolized via CYP2C9, few clinically relevant changes in their plasma levels have been reported when used concomitantly with other drugs also metabolized by CYP2C9 (see Table 7.1.2 and Fig. 7.1.2).

Analgesics

Analgesics are frequently used drugs, for both acute and chronic pain treatment. In this section, interaction with commonly used analgesics will be described.

Paracetamol

Paracetamol is indicated for mild to moderate pain and fever relief. It is usually well tolerated, and its potential for interaction is low. Interaction with warfarin has been proposed, which underscores the importance of close INR monitoring when adding this drug to, or removing it from, warfarin treatment. However, short-term use and single dosages of paracetamol is safe.

Non-steroidal anti-inflammatory drugs

NSAIDs are widely used for musculoskeletal pain relief. Both selective and non-selective NSAIDs increase the risk of various adverse events. GI complications are well known and are largely due to COX-1 inhibition, while CV adverse effects are mostly COX-2-dependent. It is known that NSAIDs, mostly due to COX-2 inhibition, increase the risk of major CV events and the risk is proportional to the dose and the patient’s baseline risk. The increased risk appears early and is not attenuated by concomitant aspirin use.9

Concerning DDIs, NSAIDs increase BP, thereby potentially inhibiting the BP-lowering effect of antihypertensive drugs. The clinical relevance of such interaction is, however, unresolved. Nevertheless, aspirin used in anti-inflammatory doses (1–2g) has been shown to decrease the antihypertensive effects of captopril and enalapril in about 50% of patients, particularly in low-renin hypertensives. Still, low-dose aspirin (≤100mg daily) does not appear to affect the BP.

The combination of an NSAID with ACEIs and ARBs increases the risk of renal impairment and increased potassium levels, especially in patients with already existing renal impairment.

NSAIDs can interfere with the antiplatelet effect of low-dose aspirin, reducing the cardioprotective effects of aspirin. Additionally, the combination of NSAIDs with aspirin, as well as with other antiplatelet drugs, also increases the bleeding risk.

NSAIDs also increase the bleeding risk when used in combination with warfarin, increasing the GI bleeding risk by 2- to 4-fold. The bleeding risk is also increased with NOACs.

Naproxen and all other NSAIDs, if indicated, should be used at the lowest effective dose for the shortest possible duration.

Opioids

Morphine is recommended for severe pain and also for pain management in patients with ACS. There are several studies reporting a negative impact of morphine on the initial blood concentrations of clopidogrel, but also of ticagrelor and prasugrel. The maximal plasma concentration was generally reduced and delayed by approximately 2h with concomitant use. The suspected mechanism of interaction is reduced gut motility by morphine and impaired absorption. However, larger randomized studies investigating the impact of those findings on clinically relevant endpoints are still lacking.

The impact of other opioids on P2Y12 receptor inhibitors has not been investigated, but since all opioids reduce gut motility, the same effect could be expected.

Methadone is used for pain management and in the maintenance treatment of opioid dependency. Methadone is found to increase the risk of QTc prolongation by blocking potassium ion (hERG) channels in a concentration-dependent manner. Methadone exists most commonly as a racemic formulation, consisting of S- and R-methadone, of which S-methadone is found to be a more potent hERG inhibitor. Risk assessment prior to prescription and ECG monitoring are suggested. Furthermore, methadone is mainly metabolized by CYP3A4, and its concomitant use with CYP3A4 inhibitors (see Table 7.1.2) is contraindicated.

Antibiotics

Bacterial infections are some of the challenges encountered in the treatment of patients with CV disease, because of DDIs, among other reasons. DDIs with antibiotics are based on several mechanisms of interaction. It can be due to inhibition or induction of P-gp and CYP450 enzymes. Depending on how strong that induction or inhibition is, concentrations of the susceptible drugs can vary, leading to an increased risk of toxicity, adverse events, or treatment failure.

However, all antibiotics can lead to a change in the intestinal bacterial flora. This can influence vitamin K synthesis, thereby increasing the bleeding risk in patients on warfarin. Interactions between various antibiotics and warfarin have been reported, with important interactions involving macrolides, quinolones, and sulfonamides, all increasing the risk of bleeding.

Rifampicin is somewhat different and is probably the antibiotic with the greatest ability to cause DDIs, due to its potential to induce many CYP enzymes and P-gp. Rifampicin is not very frequently used in the Western world, but since it can lead to very important interactions, it will be mentioned briefly here. Rifampicin induces, among others, CYP1A2, 2C9, 2C19, 2D6, and 3A4. These enzymes are involved in the metabolism of many CV drugs (see Table 7.1.2). Drugs that are metabolized by these enzymes may have decreased plasma concentrations with concomitant use and also to a clinically relevant level (e.g. simvastatin, atorvastatin, amlodipine, verapamil, diltiazem, digoxin, losartan, metoprolol, dabigatran, rivaroxaban, warfarin, ticagrelor). For prodrugs like clopidogrel, concomitant treatment with rifampicin increases the concentration of the active metabolite.

Importantly, both macrolides and quinolones are reported to cause QTc prolongation, and their combination with other QTc-prolonging drugs should be avoided, if possible, and to be used with caution if not possible. This is particularly evident for erythromycin and moxifloxacin. CV drugs such as verapamil and diltiazem, by inhibiting CYP3A4, increase the concentration of macrolides such as clarithromycin and erythromycin, and an increased concentration of these drugs can further increase the risk of QTc prolongation.

Macrolides are the group of antibiotics that are responsible for most PK interactions with CV drugs, due to their pharmacological properties by inhibiting CYP3A4. Fig. 7.1.3 presents interactions between commonly used CV drugs and macrolides.

Fig. 7.1.3 Interactions with commonly used cardiovascular drugs and macrolides. Red: contraindicated/not recommended combination. Orange: consider dose reduction. Yellow: monitor for adverse effects and/or consider using a reduced dose; consider other risk factors (elderly, renal impairment). Grey: no data available.
Fig. 7.1.3 Interactions with commonly used cardiovascular drugs and macrolides. Red: contraindicated/not recommended combination. Orange: consider dose reduction. Yellow: monitor for adverse effects and/or consider using a reduced dose; consider other risk factors (elderly, renal impairment). Grey: no data available.

Fig. 7.1.3 Interactions with commonly used cardiovascular drugs and macrolides. Red: contraindicated/not recommended combination. Orange: consider dose reduction. Yellow: monitor for adverse effects and/or consider using a reduced dose; consider other risk factors (elderly, renal impairment). Grey: no data available.

Source data from Heidbuchel H, Verhamme P, Alings M et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Eur Eur Pacing Arrhythm Card Electrophysiol J Work Groups Card Pacing Arrhythm Card Cell Electrophysiol Eur Soc Cardiol. October 2015;17(10):1467–507; Steffel J, Verhamme P, Potpara TS et al. ESC Scientific Document Group. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39(16):1330–93; and other sources.

Antifungal medications and cardiovascular drugs

Antifungal drugs are widely used for the treatment of local and systemic infections. Azoles are the most commonly used antifungal drugs for systemic therapy and are of great importance in terms of DDIs. Other systemic antifungals, such as nystatin, anidulafungin, and caspofungin, have no significant interactions with the usual CV drugs.

The azoles used for systemic infections, including fluconazole, itraconazole, voriconazole, posaconazole, and ketoconazole, are CYP3A4 inhibitors, particularly itraconazole and ketoconazole which are potent inhibitors. Voriconazole and fluconazole also inhibit CYP2C9. Due to their PK properties, azoles increase considerably the risk of interactions with CV drugs, since many of these drugs are metabolized by CYP3A4 and CYP2C9. However, most published interactions with azoles are with warfarin and statins. There is still a lack of clinical data on DDIs for many other drugs (see Fig. 7.1.4). This calls for caution when azoles are used with drugs that are metabolized via the CYP3A4 and CYP2C9 pathways (see Table 7.1.2), since important theoretical interactions still exist.

Fig. 7.1.4 Interactions with commonly used cardiovascular drugs and azoles. Red: contraindicated/not recommended combination. Orange: consider dosage reduction. Yellow: monitor for adverse effects and/or consider using a reduced dose; consider other risk factors (elderly, renal impairment). White: no need for intervention/caution. Grey: no data available.
Fig. 7.1.4 Interactions with commonly used cardiovascular drugs and azoles. Red: contraindicated/not recommended combination. Orange: consider dosage reduction. Yellow: monitor for adverse effects and/or consider using a reduced dose; consider other risk factors (elderly, renal impairment). White: no need for intervention/caution. Grey: no data available.

Fig. 7.1.4 Interactions with commonly used cardiovascular drugs and azoles. Red: contraindicated/not recommended combination. Orange: consider dosage reduction. Yellow: monitor for adverse effects and/or consider using a reduced dose; consider other risk factors (elderly, renal impairment). White: no need for intervention/caution. Grey: no data available.

Source data from Heidbuchel H, Verhamme P, Alings M et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Eur Eur Pacing Arrhythm Card Electrophysiol J Work Groups Card Pacing Arrhythm Card Cell Electrophysiol Eur Soc Cardiol. October 2015;17(10):1467–507; Steffel J, Verhamme P, Potpara TS et al. ESC Scientific Document Group. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39(16):1330–93; and other sources.

Fluconazole is special, since the inhibition of CYP450 enzymes seems to be dose-dependent. Treatment with fluconazole increases the plasma concentrations of fluvastatin and, to a lesser extent, simvastatin and atorvastatin, but dosages below 200mg daily can be used with simvastatin, fluvastatin, and atorvastatin—with close monitoring of adverse events. In cases of short-term treatment with a higher dosage of fluconazole, statin treatment can be adjusted either by temporarily withholding statin therapy or reducing the statin dose. In cases of long-term fluconazole treatment, statin therapy should be changed to a statin that is not dependent on CYP3A4 metabolism (e.g. pravastatin, rosuvastatin). However, statins should not be used with potent CYP3A4 inhibitors; for clinical management, see Major drug interactions Statins, p. [link].

Miconazole is a topical antifungal agent, and clinically important interactions with warfarin through CYP2C9 have been described.

Fig. 7.1.4 shows the most important interactions between azoles and frequently used CV drugs.

Conclusion

Many drugs can interfere with the pharmacological treatment of CV diseases, but in most cases DDIs can be overcome either by dose reduction or by increased monitoring of side effects. Only in rare cases are the concomitant use of two drugs contraindicated. In order to protect patients from more side effects than necessary, focus on the most vulnerable patients, regular medication reviews, and good communication would be beneficial.

References

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6 Steffel J, Verhamme P, Potpara TS et al. ESC Scientific Document Group. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39(16):1330–93.Find this resource:

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8 Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 2006;80:565–81.Find this resource:

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Further reading

Brunton LL, Chapner BA, Knollmann BC (eds). Goodman and Gilman´s The Pharmacological Basis of Therapeutics, 12th ed. McGraw-Hill Education: New York, NY; 2011.Find this resource:

Drugs.com. Amiodarone. Available from: http://www.drugs.com [accessed 5 June 2016].

Indiana University. Drug interactions: Flockhart Table™. Available from: http://medicine.iupui.edu/clinpharm/ddis/main-table/ [accessed 10 September 2018].

Preston CL (ed). Stockley’s Drug Interactions, 11th ed. Pharmaceutical Press: London; 2016.Find this resource: