Psychosomatics 48:537-547, November-December
doi: 10.1176/appi.psy.48.6.537
© 2007 Academy of Psychosomatic Medicine
Cardiovascular Medications
Scott Williams, M.D.,
Gary Wynn, M.D.,
Kelly Cozza, M.D., and
Neil B. Sandson, M.D.
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INTRODUCTION
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The body of evidence supporting aggressive control of cardiovascular risk factors such as blood pressure and cholesterol has resulted in polypharmacy becoming the norm. Beyond cardiovascular risk factors, other comorbidities, such as depression (with incidences as high as 31% in the first year post-myocardial infarction)1 add to the tendency toward polypharmacy. Many cardiovascular medications are substrates, inducers, or inhibitors of the cytochrome P450 (CYP) system, leaving significant potential for drug–drug interactions.2 The following is a review of the known and potential interactions among many commonly prescribed cardiovascular agents, with specific emphasis on antihypertensive agents, antiarrhythmics, anticoagulants, and cholesterol-lowering agents.
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BETA-BLOCKERS
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Beta-blockers are some of the most widely prescribed antihypertensives and are the standard of care in patients with congestive heart failure. The metabolism of these medications varies throughout the class, but only those that have significant CYP450-system interactions will be discussed in detail here (Table 1).
Carvedilol (Coreg)
Carvedilol, a nonselective beta-blocker indicated for the treatment of mild-to-moderate congestive heart failure, has also been used extensively to reduce mortality after myocardial infarction.2 It is primarily metabolized by CYP 2D6, with minor contributions from CYP 1A2, 2C9, 2C19, 2E1, and 3A4. Carvedilol has no known inhibition or induction of metabolic enzymes. Fluoxetine, a potent CYP 2D6 inhibitor, has been shown to increase plasma concentrations of carvedilol in vivo by 77%, although this appears to be a stereospecific isomer effect, with inactive R-carvedilol being the affected enantiomer. Clinically, this did not result in significant blood pressure or heart-rate changes.3 More worrisome, given carvedilol’s multienzyme metabolism, would be an interaction with a "pan-inhibitor" such as ritonavir, likely resulting in significantly elevated levels of carvedilol.
Propranolol (Inderal)
Propranolol is a nonselective beta-blocker used for the treatment of a variety of disorders, including hypertension, essential tremor, migraines, performance anxiety, and neuroleptic-induced akathisia. Propranolol is metabolized by CYP 2D6, with minor activity via 1A2 and 2C19.
Fluvoxamine (Luvox), a potent inhibitor of 1A2 and 2C19 and a mild inhibitor of 2D6, can increase plasma levels of propranolol, since all metabolic routes are inhibited.4 This interaction could potentiate the effect of propranolol, resulting in hypotension or other deleterious side effects.
There are also potentially serious interactions between propranolol and phenothiazines such as thioridazine (Mellaril), chlorpromazine (Thorazine), and the anti-emetic promethazine (Phenergan).5 The phenothiazine class is primarily metabolized at CYP 2D6, with potent auto-inhibition of 2D6. Other potent CYP 2D6 inhibitors include fluoxetine (Prozac), paroxetine (Paxil), bupropion (Wellbutrin), and cimetidine (Tagamet). Concomitant use of a phenothiazine and propranolol can result in elevated levels of both medications caused by CYP 2D6 inhibition.5 The elevated plasma levels of a phenothiazine and propranolol could potentiate the risk of QT prolongation, cardiac arrhythmias, and hypotension due to elevated levels of both medications.6 The more clinically relevant interactions include the use of propranolol with promethazine. Although not contraindicated, caution is advised when prescribing propranolol with promethazine, because studies demonstrate inhibition of metabolism, leading to increased plasma levels of both medications.6,7
Propranolol and its 4-hydroxy propranolol metabolite are also moderate inhibitors of 2D6. This inhibition may lead to increased levels of psychotropic medications such as chlorpromazine and promethazine, that are dependent on 2D6, although there are scarce clinical data to assess such an interaction.8
Metoprolol (Lopressor, Toprol XL)
Metoprolol is a cardioselective beta-blocker that has been shown to reduce mortality in patients with heart disease.9 Metoprolol is metabolized primarily via CYP 2D6. Potent inhibitors of CYP 2D6, such as quinidine and ritonavir, may greatly reduce metoprolol’s metabolism and enhance its effects.9,10 Hemeryck et al.11 studied concomitant metoprolol and paroxetine administration in healthy volunteers and found that with repeated dosing of paroxetine, a potent CYP 2D6 inhibitor, plasma levels of metoprolol were significantly elevated, and time-to-elimination was prolonged. There have been case reports of interactions between metoprolol and paroxetine leading to increased beta blockade and bradycardia. Metoprolol’s active (S)-enantiomer was found to accumulate in these subjects, which can lead to prolonged bradycardia, exercise intolerance, and an increase in side effects such as fatigue, headache, and gastrointestinal symptoms. There is also a case report of severe bradycardia with concomitant bupropion and metoprolol administration thought to be secondary to bupropion’s 2D6 inhibition.12 Although there are some in vitro data to suggest interactions between metoprolol and fluoxetine or fluvoxamine, there are few clinical data to support any significant in vivo effect.13 Metoprolol is not known to inhibit or induce any P450 enzymes, nor are there any known excretion or absorption interactions.
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CALCIUM-CHANNEL BLOCKERS
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Calcium-channel blockers (CCBs) act through voltage-gated L calcium channels via the  -1 subunit. Dihydropyridine CCBs, including nifedipine, antagonize voltage-dependent interactions, whereas diltiazem and verapamil antagonize frequency-dependent interactions. Calcium-channel blockade is not uniformly seen across tissue types, and certain CCBs have differential affinities for various tissues. For example, nimodipine crosses the blood–brain barrier and is highly selective for cerebral vasculature.
In addition to its antihypertensive effects, calcium-channel modulation is important in seizure prevention, mood-stabilization, and pain control.14 A majority of CCBs are metabolized primarily through CYP 3A4 (see Table 2), making them sensitive to potent 3A4 inhibitors like clarithromycin (Biaxin) and St. John’s wort, and 3A4 inducers, such as carbamazepine (Tegretol) and rifampin (Rifadin).15
Nifedipine (Adalat, Procardia)
Nifedipine is a first-generation dihydropyridine, used for hypertension and the prevention of angina symptoms. Primarily metabolized by CYP 3A4,16 nifedipine is vulnerable to drug interactions with potent CYP 3A4 inhibitors and inducers. Several case reports detailing these effects can be found in the literature. For instance, Azaz-Livshits et al.17 discuss an elderly woman taking nifedipine for hypertension who was started on fluoxetine for symptoms of fatigue, depression, and weakness. This combination led to significant worsening of weakness, orthostatic hypotension, and tachycardia, resulting in hospital admission. The authors concluded that fluoxetine’s inhibition of CYP 3A4 led to her condition.
There are also excretion interactions with nifedipine, since it affects renal sodium balance. Lithium has a narrow therapeutic index, and nifedipine, along with the non-dihydropyridine CCBs have been shown to increase lithium concentrations. In two studies of lithium clearance,18,19 the short-term and long-term effects of concomitant nifedipine use were evaluated. The 4-week study noted no change in lithium clearance, but the long-term study noted a 30% decrease in lithium clearance by 12 weeks.18 Also, a case report did note a possible nifedipine–lithium interaction related to reduced lithium-clearance from concomitant nifedipine therapy.19
Nimodipine (Nimotop)
Nimodipine is a dihydropyridine CCB used in the treatment of subarachnoid hemorrhage. It is primarily metabolized by CYP 3A4 and is thus affected by medications that induce or inhibit this enzyme. Tartara et al.20 investigated the effects of several anticonvulsant medications with co-administration of nimodipine. CYP 3A4 inducers carbamazepine and phenytoin (Dilantin) decreased the area under the curve (AUC) time of nimodipine by sevenfold. Valproate (Depakote), a CYP 3A4 inhibitor, was found to increase the AUC of nimodipine by about 50%.20 Nimodipine must be prescribed with caution with a CYP 3A4 inhibitor or inducer.
Pharmacodynamically, there is overlap of side-effect profiles for CCBs and anticonvulsant medications. These combined effects may increase the risk of peripheral edema.21 Nimodipine is not known to inhibit or induce any P450 enzymes, nor are there any absorption interactions.
Diltiazem (Cardizem, Tiazac)
Diltiazem, a benzothiazepine derivative, is a non-dihydropyridine CCB used for hypertension and atrial fibrillation. It undergoes metabolism primarily via oxidation at CYP 3A4, with minor contributions from 2D6 and 2E1. Diltiazem is also an inhibitor of CYP 3A4. The combination of diltiazem with 3A4-dependent triazolo-benzodiazepines such as midazolam (Versed), alprazolam (Xanax), or triazolam (Halcion) may prolong the half-life of these sedatives. Ahonen et al.22 observed the combination of midazolam and diltiazem in a study of coronary-artery bypass patients. The measured half-life of midazolam was 43% longer when combined with diltiazem, leading to a significantly longer time to extubation. Diltiazem, and, to a lesser extent, verapamil, have been shown to increase the AUC of buspirone and potentiate its side effects in a randomized, placebo-controlled, three-phase crossover study of nine healthy volunteers. This was thought to be due to the modulation of the first-pass metabolism via CYP 3A4 inhibition.23
Pharmacodynamically, there have been case reports of diltiazem interactions with lithium caused by the additive calcium-antagonism effects of both drugs.24 In one case, acute psychosis was attributed to a putative synergistic interaction between diltiazem and lithium, although the exact mechanism of action was not known. The serum lithium concentration was unchanged, so the authors felt that the additive calcium antagonism was to blame for the neurotoxicity.25
Verapamil (Calan, Covera, Verelan)
Verapamil is a phenylalkamine CCB metabolized by CYP 3A4, 3A5, 2C8, 1A2, and 2E1. There are no significant 3A4-inhibitors that have been shown to increase plasma verapamil concentration, but carbamazepine can act as a CYP 3A4-inducer, resulting in decreased plasma concentrations of verapamil. Also, verapamil inhibits CYP 3A4, which can increase carbamazepine levels, resulting in potential toxicity.26 CYP 3A4-inhibition can also enhance the effect of 3A4-dependent triazolo-benzodiazepines such as alprazolam and triazolam, leading to increased plasma levels and oversedation.27 There are no other known pharmacodynamic interactions. Like diltiazem, verapamil has also been shown to interact with lithium, leading to lithium toxicity.28
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ANGIOTENSIN-CONVERTING ENZYME INHIBITORS
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Angiotensin-converting enzyme (ACE) inhibitors are named for their interference of the conversion of angiotensin I to angiotensin II. Their metabolism is not fully understood, but the CYP450 system is thought to play an insignificant role (see Table 3). As such, CYP450 drug–drug interactions are not common, but in vivo data suggest pharmacokinetic interactions with regard to elimination and pharmacodynamic interactions with regard to additive hypotensive effects.
Captopril (Capoten)
There is a case report of postural hypotension and syncope in a patient receiving chlorpromazine and captopril.29 The mechanism of action remains unclear, and this may have been an idiosyncratic reaction, but the proposed synergistic effects led to a >80mm-Hg drop in supine systolic arterial blood pressure when compared with chlorpromazine alone, with exaggerated postural hypotension. There is a theoretical risk of this interaction with other ACE inhibitors, but there are few supporting published data.
Enalapril (Vasotec)
In another case report detailing the additive hypotensive effects of ACE inhibitors and antipsychotic medications, patients receiving clozapine (Clozaril) with enalapril experienced orthostatic symptoms and syncope.30 ACE inhibitors have been shown to have interactions with tricyclic antidepressants, as well. Despite an incomplete knowledge of the metabolism of enalapril, it has been shown that the addition of clomipramine (Anafranil) to enalapril at steady-state can result in clomipramine toxicity.31
Lisinopril (Zestril)
Although there are no known CYP450 interactions with the co-administration of lisinopril and psychotropic medications, there are excretion interactions worth noting. Lisinopril administration may result in lithium toxicity by increasing the resorption of lithium from the renal tubule. There are multiple case reports describing lithium toxicity in patients who were at steady-state before ACE-inhibitor therapy was initiated.32–34 This interaction was studied systematically in a case–control trial. In a group of 20 patients, the average increase in serum lithium concentration was 36.1%, with four patients developing signs of toxicity.35 Although it is likely that altered elimination of lithium by ACE inhibitors is a class effect, there are few supporting clinical data. DasGupta et al.36 systematically studied enalapril and lithium and found no demonstrable drug interactions, although limitations to this study included a short duration and low serum lithium levels before the addition of enalapril.36
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ANGIOTENSIN RECEPTOR-BLOCKERS
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Angiotensin receptor-blockers (ARB) are some of the newest antihypertensives on the market today; they include candesartan (Atacand), irbesartan (Avapro), olmesartan (Benicar), losartan (Cozaar), and valsartan (Diovan). (See Table 3). They are used frequently in patients with chronic kidney disease and heart failure, especially when ACE inhibitors are not tolerated because of side effects, such as chronic cough. Compared with other classes of agents, ARBs have a low potential for drug–drug interactions. Within this class, losartan and irbesartan have the greatest affinity for the P450 system, and, along with valsartan, have metabolic activity via CYP 2C9. Although there is the potential for psychotropic drug interactions (i.e., fluoxetine’s inhibition of CYP 2C9 or carbamazepine as an inducer of 2C9), to date there have been no studies or reports to indicate a clinically significant metabolic interaction that would limit the use of ARBs in conjunction with psychotropics.37 ARBs are not known to inhibit or induce any CYP isoenzymes, and there are no known pharmacodynamic interactions.
Like ACE inhibitors, ARBs have a potential elimination interaction with lithium. Through enhancing absorption and decreasing excretion, ARBs may increase lithium levels. This elimination interaction has only been reported with the co-administration of losartan and lithium,38 but, given similar elimination effects among ARBs, the potential may exist for the entire class.
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DIURETICS
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Diuretics are common first-line agents for control of hypertension, and they are frequently used for symptomatic relief in heart failure.39 Diuretics are divided into the following six categories: 1) carbonic anhydrase inhibitors, including acetazolamide (Diamox); 2) osmotic diuretics, including mannitol (Osmitrol); 3) loop diuretics, such as furosemide (Lasix) and bumetanide (Bumex); 4) thiazide diuretics, including hydrochlorothiazide (Oretic) and metolazone (Zaroxolyn); 5) potassium-sparing diuretics, such as amiloride (Midamor), triamterene (Dyrenium), spironolactone (Aldactone), and eplerenone (Inspra); and 6) antidiuretic hormone-antagonists, including lithium, demeclocycline (Declomycin), and ethanol.39 Because of competing actions at tubular sites, all diuretics have been associated with variations in plasma lithium levels. In a review of 22 patients with lithium overdose, 15 instances were directly attributed to concomitant diuretic use.40 Thiazide diuretics are associated with the greatest increase in lithium levels, up to as much as 40% over baseline. Loop diuretics and potassium-sparing diuretics have negligible effects, whereas osmotic diuretics and carbonic anhydrase inhibitors may decrease lithium levels.41,42 Various drug interactions involving diuretics and psychotropic medications are detailed below.
Acetazolamide (Diamox)
Acetazolamide is a carbonic anhydrase inhibitor used in a variety of clinical settings, including the treatment of glaucoma, altitude sickness, epilepsy, and congestive heart failure. Despite 100% unchanged excretion in urine, acetazolamide appears to inhibit hepatic metabolism. There are data to suggest that concomitant use of acetazolamide and carbamazepine may increase plasma cabamazepine levels and lead to toxicity.43
Furosemide (Lasix)
Furosemide is a widely used, potent, loop diuretic that may alter the concentration of many electrolytes. Furosemide has minimal hepatic metabolism and no known CYP450 interactions. Pharmacodynamic interactions involving electrolyte disturbances, such as hypokalemia, hypomagnesemia, hyponatremia, and hypocalcemia have all been reported.44 Hyponatremia may be exacerbated by co-administration with fluoxetine. There have been two case reports of patients developing severe hyponatremia resulting in death while receiving this combination. Although a causal relationship was not fully established, these case reports and others of both diuretic-induced and SSRI-induced hyponatremia suggest possible risk factors, including increased age and female sex.45,46
Amiloride (Midamor)
There are no known clinically relevant drug interactions between amiloride and psychotropic medications, but in vitro studies do suggest a competitive binding by amitriptyline to the pyrazine binding site of sodium channels. The significance of this is not known.47
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ANTIARRHYTHMICS
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The antiarrhythmics are a potent and diverse group of medications used for a variety of cardiovascular disorders. The interactions between psychotropic medications and antiarrhythmics can be some of the most clinically important because of their narrow therapeutic indices and potentially life-threatening side effects. Caution should be used when co-administering agents from the classes detailed below (see Table 4), especially if there is concern for additive QTc prolongation.48
Quinidine (generic)
Quinidine is a Class IA antiarrhythmic drug used in atrial fibrillation and ventricular arrhythmias. Quinidine is primarily metabolized via CYP 3A4. It is a potent inhibitor of CYP 2D6. CYP 3A4 inhibitors such as paroxetine, nefazodone (Serzone), diltiazem, ketoconazole (Nizoral), clarithromycin, erythromycin, and grapefruit juice may increase quinidine levels, resulting in toxicity. Quinidine’s potent CYP 2D6 inhibition may lead to elevated plasma concentrations of CYP 2D6 substrates such as fluvoxamine, paroxetine, venlafaxine (Effexor), and haloperidol (Haldol).49–51 Quinidine also exerts potent P-glycoprotein effects, and studies are being conducted in-vivo to assess the importance of this finding.52
Mexiletine (Mexitil)
Mexiletine is a Class IB antiarrhythmic agent, with a narrow therapeutic index, used for controlling ventricular arrhythmias. Mexiletine undergoes metabolism via CYP 2D6, with some metabolism through 1A2. Kusumoto et al.53 found that concomitant administration of mexiletine with fluvoxamine, a CYP 1A2 and 2D6 inhibitor, resulted in significantly increased mexiletine peak concentrations. Also, in-vitro data suggest possible interactions when mexiletine is co-administered with paroxetine, fluoxetine, desipramine, and thioridazine, but clinical data are lacking.54
Mexiletine is not known to inhibit or induce hepatic enzymes, nor are there any significant elimination interactions.
Flecainide (Tambocor)
Flecainide, a Class IC antiarrhythmic used for a variety of supraventricular and ventricular arrhythmias, undergoes oxidative metabolism via CYP 2D6 and 1A2. Inhibition of CYP 2D6 by medications such as paroxetine, fluoxetine, sertraline (Zoloft), and citalopram (Celexa) may result in elevated flecainide levels.55 Flecainide may inhibit 2D6, but the significance of this is not known. Flecainide does not induce any P450 enzymes, and there are no known elimination interactions.
Propafenone (Rythmol)
Propafenone is a Class IC antiarrhythmic drug that is metabolized by CYP 2D6, with minor contribution from 1A2 and 3A4. As with flecainide, selective serotonin reuptake inhibitors (SSRIs) and other medications that inhibit 2D6 may lead to elevated propafenone levels.56 Propafenone is also an inhibitor of CYP 1A2 and 2D6. Katz57 reported a case of desipramine toxicity after the addition of propafenone, which likely resulted from CYP 2D6 inhibition. There are no known elimination interactions.
Ibutilide (Corvert)
Ibutilide is a Class III antiarrhythmic that is commonly used to convert atrial fibrillation to normal sinus rhythm. The metabolic profile is not completely understood, but there are no known data supporting significant CYP450 interactions. Pharmacodynamically, it has the effect of increasing the QT interval and should be used with caution in patients with a prolonged QT interval. Tricyclic antidepressants and other medications that can also increase the QT interval should be avoided.58
Amiodarone (Cordarone, Pacerone)
Amiodarone is a Class III antiarrhythmic used for a variety of arrhythmias and for emergency rhythm-conversion. It is metabolized extensively by CYP 2C8 and 3A4, so caution should be used when prescribing concomitant SSRI therapy that can inhibit 3A4. Amiodarone also inhibits CYP 1A2, 2C9, 2D6, and 3A4. Although there are multiple enzymes that are both substrate for and inhibited by amiodarone, few data exist with regard to hepatic enzyme-dependent drug–drug interactions with psychotropics.
Amiodarone does appear to have a number of non-CYP450 interactions. Trazodone is contraindicated with amiodarone, given that there are case reports of polymorphic ventricular tachycardia and torsade de pointes secondary to QT prolongation from the co-administration of these two medications.59,60 The same may be true for tricyclic antidepressants, so caution should be exercised when these agents are used.
Dofetilide (Tikosyn)
Dofetilide is a Class III antiarrhythmic agent that is approved for conversion and maintenance of sinus rhythm in patients with atrial fibrillation and flutter. It is mainly excreted unchanged in the urine via the cationic transport system, and there are no reports of hepatic metabolic interactions. Prochlorperazine (Compazine) can inhibit elimination, however, so this combination should be avoided.61
Digoxin (Lanoxin)
Digoxin is a Class IV antiarrhythmic agent with a narrow therapeutic window, used for increasing ionotropy in congestive heart failure as well as for control of supraventricular arrhythmias. The metabolism of digoxin is not well understood, but only a small fraction occurs via hepatic oxidation. Known interactions with benzodiazepines occur through mechanisms that are also not well understood. Although the interaction has been reported with alprazolam,62 other benzodiazepines may also produce changes in the serum concentration of digoxin.63 Digoxin concentration may also be increased when fluoxetine, paroxetine, or nefazodone are added.64 Insofar as digoxin is a substrate of the extruding P-glycoprotein pump, these increases are likely to be attributable to the inhibition of pump activity by these drugs, thus increasing intestinal absorption of digoxin. Increases in digoxin concentration of up to 30% have been seen with nefazodone and paroxetine; however, there is one case of fluoxetine producing a threefold increase in the digoxin level.65 Monitoring of digoxin levels is important when titrating these antidepressant medications.
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ANTICOAGULANT AGENTS
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With an aging population, the increasing risk of myocardial infarction and stroke has led to an increasing number of patients’ receiving anticoagulant therapy. The most commonly prescribed anticoagulant is warfarin, but many newer agents are being used with increasing frequency for a variety of disease processes, including claudication, prevention of in-stent re-stenosis after percutaneous interventions, and the treatment of heparin-induced thrombocytopenia. These medications are detailed below. (See Table 5.)
Warfarin (Coumadin)
Warfarin has a narrow therapeutic index and a greater than 20-fold variation in maintenance dose, requiring diligent monitoring of patients’ international normalized ratios (INRs). In addition to age, gender, vitamin K intake, and co-administration of other medicines, genetic factors are a major contributor to dose variation and patient hazards.66 DNA-sequence polymorphisms in CYP 2C9, which metabolizes the active S form, are found in 35% of patients and cause a doubling or tripling of the warfarin serum half-life.67 The considerably less active R form is metabolized by multiple enzymes, including 1A2, 2C8, 2C18, 2C19, and 3A4. A combination of genetic testing for CYP 2C9 polymorphism and the vitamin K receptor (VKORC1),68 warfarin’s site of action, may allow a clinical provider a more accurate means of estimating dosage requirements.69
The Physicians’ Desk Reference lists three pages of possible interactions with warfarin. Of these, a variety of psychotropics, including fluvoxamine, fluoxetine, and sertraline may lead to increased warfarin levels via inhibition of 2C9. However, the clinically important interactions have only been shown with fluoxetine and fluvoxamine.70 In addition to inhibition of 2C9, fluvoxamine has the potential to inhibit 1A2, 2C9, and 3A4. This interaction has led to sustained, elevated inhibition of the clotting cascade.71 Also, co-administration of warfarin with CYP 3A4-inducers such as carbamazepine should be avoided because the interaction could lead to decreased efficacy, with increased coagulation.72
Paroxetine, however, has been shown to increase bleeding with warfarin via an undetermined mechanism. In one study, 5 out of 27 healthy volunteers developed clinically significant bleeding without associated changes in their prothrombin times or their INRs.73 In contrast, trazodone has been shown to decrease prothrombin time and partial thromboplastin time, although the mechanism is not understood, and the interaction is not thought to be very significant.74 There are also case reports suggesting that tricyclic antidepressant use in conjunction with warfarin can increase prothrombin time and increase bleeding. The putative mechanism is via reduced absorption and decreased metabolism, but it is unlikely to be clinically significant.75
Ticlopidine (Ticlid)
Ticlopidine is an antiplatelet agent that works via an incompletely understood mechanism. Ticlodipine is extensively metabolized via the liver, although the exact mechanism has not been fully elucidated, and it is not known how inhibitors and inducers of the CYP450 system affect ticlodipine metabolism.
Ticlopidine does appear to inhibit (in descending order of potency) CYP 2B6, 2C19, 2D6, 1A2, and 2C9.76 There have been case reports of co-administration of carbamazepine and ticlodipine resulting in carbamazepine toxicity and reports of ticlopidine affecting phenytoin clearance.77 There is also a theoretical possibility of a similar interaction with duloxetine, but there are currently no supporting data.
Other Anticoagulant Agents
It is important to note that there are no published data to suggest a potential for interactions between heparin and psychotropic medications. Newer medications, such as argatroban, a direct thrombin inhibitor, have also not shown any potential for interaction with psychotropics, even though the drug is metabolized by CYP 3A4.
The anti-platelet agents cilostazol (Pletal) and clopidogrel (Plavix) also appear to be devoid of hepatic interactions. Cilostazol, an anti-platelet agent metabolized by CYP3A4 and 2C19, does not appear to have any interactions via hepatic metabolism. Clopidogrel, another anti-platelet agent, on the other hand, appears to be an inhibitor of CYP 2C9, 2B6, and 2C19 at high concentrations. Although there is the potential for interaction with medications such as phenytoin, nefazodone, fluoxetine, or other SSRIs, there are currently no relevant reports in the literature.
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CHOLESTEROL-LOWERING AGENTS
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Over the past decade, recommendations regarding cholesterol management have become increasingly stringent, resulting in greater numbers of individuals’ receiving a variety of lipid-lower agents. Given that many of the newer psychotropic medications, including atypical neuroleptics, alter the lipid profile, the prevalence of concomitant psychotropic and cholesterol-lowering medications seems to be rising. Hydroxymethylglutaryl-coenzyme A reductase inhibitors (HMG-CoA reductase inhibitors), or statins, decrease plasma cholesterol levels by inhibiting cholesterol synthesis in the liver and are the most commonly prescribed cholesterol-lowering medications today. Despite the fact that many cholesterol-lowering medications are metabolized by the CYP450 system, there are a limited number of case reports or clinical trials that describe the outcome of concomitant statin and psychotropic administration.
Statins
Most statins, except pravastatin (Pravachol) and rosuvastatin (Crestor), are primarily metabolized by CYP 3A4 (see Table 6). Statins metabolized primarily via CYP 3A4, including simvastatin (Zocor), lovastatin (Mevacor), and atorvastatin (Lipitor) may lead to increased risk of toxicity, producing symptoms of muscle aches, myopathy, and rhabdomyolysis when combined with potent CYP 3A4 inhibitors such as itraconazole (Sporanox), ketoconazole, ritonavir, ciprofloxacin (Cipro), clarithromycin, erythromycin, cyclosporine, efavirenz (Sustiva), lopinavir/ritonavir (Kaletra), nefazodone, and grapefruit juice.78–80
There are many moderate or mild inhibitors of CYP 3A4 that are simultaneously prescribed more frequently than the potent inhibitors with statins, and these include beta-blockers and calcium-channel blockers.
Rosuvastatin and fluvastatin (Lescol) are either wholly or partially dependent on CYP 2C9 for metabolism. Potent inhibitors of CYP 2C9 include fluconazole (Diflucan), fluvoxamine, and ritonavir, which may also lead to statin toxicity. Although atorvastatin, fluvastatin, and simvastatin show moderate-to-potent inhibition of CYP 2C9 or 2C8, the remaining statins do not inhibit or induce any hepatic enzyme.
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SUMMARY
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As the above discussion reveals, there are numerous pharmacokinetic and pharmacodynamic drug interactions between cardiovascular drugs, psychotropics, and numerous other medications. Most beta-blockers are dependent upon cytochrome 2D6 for their metabolism, which may lead to drug toxicity if co-administered with potent 2D6 inhibitors such as paroxetine, fluoxetine, or quinidine. Calcium-channel blockers are dependent on CYP 3A4 for metabolism and are therefore subject to interactions with potent inhibitors of CYP 3A4, such as clarithromycin, erythromycin, nefazodone, and ciprofloxacin. Diltiazem is a calcium-channel blocker that also is a potent CYP 3A4 inhibitor. Lithium may have pharmacokinetic interactions in the elimination phase of metabolism with angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers. Diuretics also interact with lithium directly in the kidney. Since many psychotropics, particularly the tricyclic antidepressants, affect cardiac conduction, special care needs to be taken with antiarrhythmic medications, since there may be a synergistic pharmacodynamic effect. Also, most antiarrhythmics are metabolized at cytochrome 2D6 and are therefore sensitive to drug interactions with potent inhibitors of CYP 2D6 metabolism such as paroxetine and fluoxetine. Warfarin and digoxin have complicated metabolic profiles and always warrant careful monitoring when co-administered with any other medications. Atorvastatin, lovastatin, and simvastatin are dependent on CYP 3A4, and potent inhibition of these enzymes have frequently led to statin toxicity. Fluvastatin and rosuvastatin are dependent on CYP 2C9 and may be subject to interaction with inhibitors of that enzyme.
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ACKNOWLEDGMENTS
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Scott G. Williams, M.D., is a teaching fellow at the Uniformed Services University in Bethesda, MD, and is a senior resident in the departments of Psychiatry and Internal Medicine at Walter Reed Army Medical Center, Washington, DC.
Gary H. Wynn, M.D., is an internist and psychiatrist who is Assistant Professor of Psychiatry at the Uniformed Services University in Bethesda, MD, and is Assistant Chief of Inpatient Psychiatry Services at Walter Reed Army Medical Center, Washington, DC.
Kelly L. Cozza, M.D., F.A.P.M. is Associate Professor of Psychiatry at the Uniformed Services University in Bethesda, MD, and psychiatric consultant to the Dept. of Psychiatry at Walter Reed Army Medical Center in Washington, DC, and is a co-author of The Concise Guide to Drug Interaction Principles for Medical Practice (American Psychiatric Publishing, Inc.).
Neil B. Sandson, M.D., is a psychiatrist working within the Veterans Affairs Maryland Health Care System, and is a Clinical Assistant Professor in the Department of Psychiatry at the University of Maryland School of Medicine. Dr. Sandson is also Column Editor for the Psychosomatics Med.–Psych. Drug–Drug Interaction series.
The authors thank Howard C. Coleman, B.S., B.A.; CEO, Genelex Corporation; Seattle, WA, for his review and comments pertaining to pharmacogenetic testing and warfarin.
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INTRODUCTION
BETA-BLOCKERS
