Avoiding Serious Drug Interactions

Digoxin, calcium channel blockers, phenytoin, ACE inhibitors, metronidazole, loop diuretics, phenothiazines, carbamazepine, rofecoxib, and sildenafil all can be quite hazardous if administered concurrently with certain other drugs. The authors provide a refresher course on precautions.

By RaeAnn Hamilton, MD, and Charles S. Graffeo, MD

 
In this age of polypharmacy and the introduction of new drugs on the market at an ever-increasing rate, physicians need to be aware of potential drug interactions. Many patient complaints may, in fact, be directly related to drug interactions that too often go unrecognized. Before prescribing a new medication for a patient, it is imperative to review the drugs that he or she is taking. This article will provide an overview of common drug interactions, risk factors that predispose to drug interactions, and some helpful guidelines and resources.
 

DIGOXIN

Digoxin is a cardiac glycoside that is commonly used to treat supraventricular tachyarrhythmias and congestive heart failure. It is rapidly absorbed from the gastrointestinal tract and excreted by the kidneys. About 50% to 70% of intravenous (IV) digoxin is excreted unchanged in the urine. It has a half-life of 36 to 48 hours (prolonged to 3.5 to 5 days in anuric patients) and a very narrow therapeutic window.

Digoxin crosses both the blood-brain barrier and the placenta. It also directly inhibits sodium/potassium ATPase, which results in an increase in intracellular sodium, altering the driving force for sodium-calcium exchange so that less calcium is removed from the cell. Additionally, digoxin modifies autonomic outflow by increasing vagal tone and decreasing atrioventicular node conduction.

The most dangerous drug interactions involving digoxin typically cause an increase in serum digoxin levels. This is usually a result of an alteration in the metabolism or excretion of the drug. It is important for physicians to recognize signs of toxicity because of the potentially fatal cardiac arrhythmias that may develop. Adverse reactions include premature ventricular contractions (most common), ventricular tachycardia, severe bradycardia, heart block, arrhythmias, anorexia, nausea, vomiting, diarrhea, and central nervous system (CNS) effects (such as visual disturbances, weakness, and confusion). The elderly and those with pre-existing medical conditions, such as heart disease, renal dysfunction, hepatic dysfunction, hypothyroidism, and chronic obstructive pulmonary disease, are at increased risk for toxicity.

Although there are more than 20 drugs that interact with digoxin (see table below), the most common drug interactions associated with digoxin toxicity include quinidine and calcium channel blockers. Amiodarone, azole antifungal drugs, clarithromycin, cyclosporine, erythromycin, flecainide, and propafenone all introduce the risk of increasing digoxin to toxic levels by decreasing its renal clearance. One in 10 patients converts 40% or more of oral digoxin to an inactive reduction product (dihydrodigoxin) via bacteria in the gut. Therefore, certain antibiotics (tetracycline, erythromycin, clarithromycin, and possibly other macrolides) increase digoxin absorption by inactivating these bacteria.

Antacids and bile acid-binding resins must be given two hours after digoxin is administered because these drugs are known to decrease the absorption of digoxin. Metoclopramide speeds gastrointestinal transit time and reduces serum digoxin levels secondary to decreased absorption. Conversely, anticholinergics, which are known to slow gastrointestinal transit time, increase digoxin levels substantially. Potassium or magnesium depletion sensitizes the myocardium to digoxin. Therefore, patients with malnutrition, diarrhea, and prolonged vomiting, as well as patients being treated with corticosteroids, loop and thiazide diuretics, amphotericin B, antacids, or dialysis, may show signs of digoxin toxicity despite normal serum concentrations.

Drugs known to cause bradycardia, such as beta blockers and calcium channel blockers (especially diltiazem, verapamil, and bepridil), may potentiate the development of serious bradyarrhythmias in patients taking digoxin. Cardiac arrhythmias have also been reported when digoxin is used in combination with calcium salts, sotalol, succinylcholine, and sympathomimetics.

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CALCIUM CHANNEL BLOCKERS

Diltiazem is among the most commonly used calcium channel blockers to treat hypertension, coronary artery disease, and supraventricular tachyarrhythmias. Like all calcium channel blockers, its mechanism of action is via the blockage of L-type calcium channels. By decreasing calcium influx during action potentials, these drugs cause a reduction in muscle contractility and heart rate. They also relax smooth muscle tissue in blood vessels, the uterus, bronchi, and gastrointestinal tract. In addition, they selectively reduce the heart rate during tachycardia involving the atrioventricular node, with little or no effect on normal node conduction.

Calcium channel blockers are contraindicated in sick sinus syndrome, second- and third-degree heart block, Wolff-Parkinson-White (WPW) syndrome, severe hypotension or cardiogenic shock, and acute myocardial infarction (AMI). Common side effects with these drugs include edema, headache, dizziness, asthenia, flushing, nausea, constipation, and rash. First-degree atrioventricular block, bradycardia, hypotension, syncope, and liver abnormalities have also been described.

Calcium channel blockers have numerous potential drug interactions. There is an increased risk of hypotension, bradycardia, and atrioventricular nodal block when these drugs are given in combination with amiodarone, azole antifungal drugs, beta blockers, delavirdine, fluvoxamine, nefazodone, protease inhibitors, and quinidine. Protease inhibitors are specifically contraindicated with the calcium channel blocker bepridil. It also should not be given together with, or within a few hours of, IV beta blockers. Cimetidine and erythromycin in combination cause an increased risk of bradycardia and hypotension, while cimetidine and flecainide may cause bradycardia and atrioventricular nodal block.

A decrease in calcium channel blocker efficacy is seen when used in combination with barbiturates, carbamazepine, phenytoin, rifabutin, and rifampin. The statin drugs have been shown to interact with diltiazem, with resulting myopathies and rhabdomyolysis. Use with benzodiazepines may result in increased CNS depression. Cyclosporine, digoxin, and theophylline all need to have their levels monitored when used in combination with calcium channel blockers because they may reach toxic concentrations.
 

PHENYTOIN

Phenytoin is commonly used to treat status epilepticus and tonic-clonic, psychomotor, and neurosurgically induced seizures. Its mechanism of action is to suppress repetitive action potentials in epileptic foci in the brain by blocking sodium channels in neuronal membranes.

Phenytoin's oral bioavailability is variable due to wide fluctuations in first-pass metabolism. It binds extensively to plasma proteins (97% to 98%), and any free (unbound) drug is available to compete for binding with other drugs such as warfarin. It is contraindicated in patients with heart block and sinus bradycardia.

The effects of phenytoin are potentiated by acute alcohol ingestion and antagonized by chronic alcohol ingestion. Common side effects associated with its use include nystagmus, drowsiness, ataxia, gastrointestinal disturbances, gingival hyperplasia, rash, hypertrichosis, and a systemic lupus erythematosus-type syndrome. Osteomalacia, blood dyscrasias, lymphadenopathy, hepatic disease, and hyperglycemia are also known to occur.

Phenytoin's main interaction with other drugs is based upon their effect on hepatic metabolism (see table below). Drugs that inhibit hepatic metabolism cause phenytoin levels to rise, increasing the risk of toxicity. These drugs include amiodarone, cimetidine, isoniazid, and metronidazole. Drugs that increase hepatic metabolism of phenytoin, such as carbamazepine, doxorubicin, estrogens, oral contraceptives, phenobarbital, and rifampin, all predispose to poor seizure control. Phenytoin is known to accelerate hepatic metabolism of acetaminophen, which increases the production of toxic metabolites. Therefore, acetaminophen use should be limited in patients taking phenytoin.

Benzodiazepines potentiate the CNS depression associated with phenytoin, and their levels should be monitored carefully. Quinolones may alter hepatic metabolism of drugs such as theophylline, warfarin, glyburide, and phenytoin, and may predispose the patient to toxic levels of these drugs. Opiate withdrawal may be precipitated when methadone is used in conjunction with phenytoin. Calcium channel blockers, cyclosporine, haloperidol, quinidine, and theophylline all have decreased efficacy secondary to lower therapeutic concentrations caused by concomitant pheytoin administration. When phenytoin is used in combination with valproic acid, its levels increase while valproic acid levels decrease. Prothrombin time (PT) or international normalized ratio (INR) must be closely monitored when phenytoin is used with warfarin because both drugs compete for protein binding, which has been shown to transiently increase INR, with a resultant risk of bleeding. With chronic use, INR and warfarin efficacy may decrease.

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ACE INHIBITORS

ACE inhibitors are commonly used to treat hypertension, diabetic renal disease, and significant left ventricular dysfunction (ejection fraction less than 40%). Their mechanism of action is to inhibit angiotensin-converting enzyme, kininase II, and peptidyl dipeptidase. This results in a reduction of angiotensin II and aldosterone and a variable increase in endogenous vasodilators such as bradykinin. Consequently, salt retention, water retention, and vascular resistance are reduced, making these drugs useful in the management of heart failure.

Patients with renal impairment, congestive heart failure, renal artery stenosis, and aortic stenosis should be closely monitored for adverse effects caused by ACE inhibitors. Hyperkalemia is fairly common in diabetic patients and those with renal insufficiency. Common adverse effects in general include cough (up to 30% of patients), headache, fatigue, diarrhea, rash, pruritus, orthostatic hypotension, dizziness, proteinuria, hyperkalemia, hyponatremia, tachycardia, dry mouth, jaundice, impotence, renal impairment, and nausea. Angioedema is one of the most potentially dangerous side effects.

There are a host of potential drug interactions with ACE inhibitors. The risk of hyperkalemia is increased when these drugs are used with cyclosporine, potassium-sparing diuretics, potassium supplements, or tacrolimus. Hypotension may occur when they are used with loop and thiazide diuretics. Hypoglycemia may occur in type 1 diabetic patients because insulin's effect is potentiated by concomitant use of ACE inhibitors. Also, there is an increased risk of nephrotoxicity and a loss of antihypertensive effectiveness when ACE inhibitors are used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase (COX)-2 inhibitors. It is suspected that a decrease in renal excretion of ACE inhibitors occurs when these drugs are used with lithium, which may result in toxicity. A severe hypersensitivity reaction has been documented with combination use with allopurinol. Captopril must be given one hour before, or four hours after, antacids because of the risk of decreased absorption from the gastrointestinal tract.
 

METRONIDAZOLE

Metronidazole is an antimicrobial agent commonly used to treat susceptible anaerobic and protozoal infections, including intra-abdominal, skin, gynecologic, bone, joint, CNS, and lower respiratory tract infections, as well as septicemia and endocarditis. Important clinical uses include treatment of trichomoniasis, giardiasis, bacterial vaginosis, and extraintestinal amoebic disease. Its bactericidal action results from the formation of toxic metabolites in the bacterial cell. It penetrates most tissues, including abscesses and the CNS, and is eliminated by hepatic metabolism.

Alcohol must be avoided during and for three days after metronidazole use because abdominal cramps, nausea, vomiting, headache, and flushing may occur. Common adverse effects include seizures, peripheral neuropathy, gastrointestinal upset, anorexia, constipation, headache, metallic taste, dysuria, cystitis, and candidal overgrowth.

Caution needs to be exercised when treating patients with HIV infection who are undergoing treatment with antiviral medications. There is an increased risk of peripheral neuropathy when metronidazole is used with didanosine, stavudine, or zalcitabine, and concomitant use with ritonavir may cause an alcohol-disulfiram-like reaction. Treating post-transplant patients with metronidazole also requires caution because levels of both cyclosporine and tacrolimus, which are commonly used with these patients, may rise, introducing the risk of neurotoxicity. Phenytoin levels must also be closely monitored to avoid toxicity. An increased risk of bleeding may occur when metronidazole is used in combination with warfarin, and therefore INRs must be monitored regularly. As with most antibiotics, metronidazole impairs the efficacy of oral contraceptives. Other forms of birth control should be advised.
 

LOOP DIURETICS

Furosemide is a very useful agent for immediate reduction of the pulmonary congestion and severe edema associated with congestive heart failure. It is also used to treat hypertension, edematous states secondary to liver failure, and severe hypercalcemia. It acts by inhibiting potassium, the co-transporter of sodium, and chloride at the loop of Henle in the kidney. A full dose may produce a massive sodium chloride diuresis and may significantly reduce blood volume. A loss of the luminal-positive potential reduces the reabsorption of divalent cations, thereby increasing calcium excretion. A large concentration of sodium at the level of the collecting tubule results in significant potassium wasting with the potential for hypokalemic alkalosis. Furosemide has also been shown to have a potent pulmonary vasodilating effect.

Loop diuretics are relatively short-acting and usually cause diuresis over the four hours following a dose. These drugs should be used very cautiously in the elderly, in pregnant or breastfeeding women, and in any patient with renal or hepatic dysfunction, diabetes, gout, or lupus. Adverse reactions include excessive diuresis, fluid or electrolyte imbalance, ototoxicity, gastrointestinal upset, dizziness, vertigo, paresthesias, orthostatic hypotension, hyperglycemia, jaundice, hyperuricemia, rash, photosensitivity, tinnitus, hearing loss, and blood dyscrasias.

There is an increased risk of hypokalemia and electrolyte abnormalities when loop diuretics are used in combination with amphotericin and digoxin. Caution must also be taken when treating asthmatic and chronic obstructive pulmonary disease patients with beta blockers and corticosteroids; the interaction with loop diuretics may potentiate the risk of hypokalemia. Hypotension has also been observed in patients being treated concomitantly with ACE inhibitors, angiotensin II receptor blockers, and thiazide diuretics. Hyperglycemia may occur in diabetic patients being treated with glyburide/metformin, insulin, or sulfonylureas, because furosemide and other loop diuretics decrease the efficacy of these drugs. Also, nephrotoxicity has been found to occur more frequently when furosemide is used in conjunction with NSAIDs and COX-2 inhibitors. Lastly, a decrease in renal excretion may cause lithium levels to rise.
 

PHENOTHIAZINES

Phenothiazines, such as promethazine, are commonly used to treat acute episodes of nausea and vomiting. They act as a histamine H1 antagonist and have a sedative and antimotion sickness effect on the CNS.

These agents must be used with caution in elders, pregnant or breastfeeding women, and patients being treated for glaucoma, gastrointestinal or urinary tract obstruction, cardiovascular or liver disease, epilepsy, peptic ulcer disease, or bone marrow depression. Phenothiazines have also been shown to alter serum pregnancy test results. Adverse reactions include drowsiness, decreased seizure threshold, cholestatic jaundice, photosensitivity, hypotension or hypertension, rash, and blood dyscrasias. Anticholinergic and extrapyramidal side effects may be particularly troublesome, and in rare cases they may be irreversible.

Phenothiazines are associated with an increased risk of arrhythmias secondary to a prolongation of the QT interval when used with class IA or III antiarrhythmics, such as astemizole, cisapride, and pimozide, or with quinolones. Patients with prolonged QT syndrome may be at particularly high risk. An increase in CNS depression may be seen when phenothiazines are used in combination with antihistamines, barbiturates, benzodiazepines, muscle relaxants, opiates, sedative/hypnotics, or tricyclic antidepressants.

There is a higher risk of extrapyramidal symptoms when phenothiazines are used with lithium, monamine oxidase (MAO) inhibitors, and metoclopramide. Insulin requirements in diabetic patients may increase. Dopamine may also have to be given at higher doses to produce the desired therapeutic effect. A higher incidence of adverse effects has been noted with concomitant use of anticholinergics. As is typical with antacids, promethazine must be given one hour prior to a phenothiazine to avoid decreased absorption.
 

CARBAMAZEPINE

Carbamazepine is used to treat generalized tonic-clonic, partial and mixed seizures, mania in bipolar disorder, and trigeminal neuralgia. It induces the formation of liver enzymes that increase its metabolism as well as the clearance rates of many other anticonvulsants. Its mechanism of action is the blocking of sodium channels in neuronal membranes.

This drug is contraindicated in patients with a history of bone marrow depression or sensitivity to tricyclic antidepressants and during or within 14 days of initiation of therapy with MAO inhibitors. Adverse reactions include aplastic anemia, bone marrow depression, diplopia, ataxia, rash, Stevens-Johnson syndrome, photosensitivity, heart failure, edema, hypotension or hypertension, and arrhythmias. Drowsiness, dizziness, nausea, liver and urinary disorders, dyspnea, lens opacities, arthralgias, and fever have also been reported.

As with phenytoin, most of carbamazepine's potential drug interactions are mediated by hepatic metabolism (see table below). There is a greater risk of toxicity when the drug is used with azole antifungals, calcium channel blockers, cimetidine, erythromycin, and valproic acid. A greater risk of breakthrough seizures has been reported when carbamazepine is given with phenytoin or acetaminophen. Acetaminophen must also be limited to less than two grams daily because it causes increased toxic metabolite formation, raising the risk of hepatic damage. An increase in CNS depression may occur with benzodiazepines. The effectiveness of cyclosporine, olanzapine, protease inhibitors, quinidine, and theophylline decreases, secondary to an induction of hepatic metabolism, when they are used with carbamazepine.

Monamine oxidase inhibitors are strictly contraindicated; their use may result in CNS overstimulation, hyperpyrexia, seizures, and even death. Concomitant lithium may result in neurotoxic adverse effects, even at therapeutic levels. Patients taking methadone may experience opiate withdrawal. Alternative forms of birth control should be recommended to women taking oral contraceptives. In patients being treated with vasopressin, use of carbamazepine potentiates an antidiuretic response. Warfarin may have to be given at higher doses to maintain its anticoagulant efficacy.

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ROFECOXIB

Rofecoxib is a part of the NSAID group of drugs that has anti-inflammatory, analgesic, and antipyretic activity. It accomplishes this by inhibiting prostaglandin synthesis selectively through the inhibition of COX-2. At therapeutic levels it does not inhibit COX-1. Of the two COX isoforms, COX-1 is found in most tissues and protects the gastric mucosa, while COX-2 is mainly induced at sites of inflammation.

Rofecoxib is indicated for the treatment of joint pain secondary to arthritis, postoperative dental pain, pain after orthopedic surgery, and primary dysmenorrhea. Its metabolism is primarily through reduction by cytosolic enzymes; the cytochrome P450 system plays only a minor role. The drug is eliminated predominantly by hepatic metabolism and excreted in the urine, with a therapeutic half-life of about 17 hours.

Rofecoxib is not recommended for patients with severe renal insufficiency because there is no safety information available, but studies have shown the elimination profile does not change in patients who undergo dialysis 48 hours after receiving the drug. It has not been studied in patients under age 18 and is therefore not recommended in pediatric patients. It also should be avoided in late pregnancy because it may cause premature closure of the ductus arteriosus and is therefore a pregnancy category C drug. It crosses both the placenta and the blood-brain barrier.

Serious complications such as bleeding, ulceration, and perforation of the gastrointestinal tract have been documented to occur at any time with or without warning symptoms. One study of patients who underwent endoscopy revealed that rofecoxib at 25 to 50 mg daily was associated with a lower percentage of gastrointestinal ulcers compared to ibuprofen at 2400 mg daily. However, there was some increase in ulceration compared to placebo. A history of peptic ulcer disease puts patients at a higher risk for complications with rofecoxib. In addition, other concomitant therapies and comorbidities may also increase the risk of gastrointestinal bleeding; these include treatment with corticosteroids or anticoagulants and smoking, alcoholism, old age, and poor overall health status.

Adverse effects include fatigue, dizziness, lower extremity edema, dyspepsia, epigastric pain, nausea, and bronchitis. Most of these occur less frequently than with ibuprofen. Anemia sometimes occurs, but rofecoxib does not affect platelet count, bleeding time, PT or partial thromboplastin time (PTT), nor does it inhibit platelet aggregation.

Drug interactions with rofecoxib are similar to those that may occur with other NSAIDs. It has been shown to diminish the antihypertensive effects of ACE inhibitors, and it can reduce the natriuretic effect of both furosemide and thiazides in some patients due to inhibition of renal prostaglandin synthesis. Lithium and methotrexate levels would need to be closely monitored because there is a decrease in their renal clearance—and therefore an increase in their concentrations—when used with rofecoxib. Rifampin, a potent inducer of hepatic metabolism, produces a 50% decrease in rofecoxib concentrations; therefore, rofecoxib's starting dose should be higher than normal (or more than 25 mg/day).

Anticoagulant activity needs to be closely monitored with concomitant rofecoxib since patients will be at increased risk for bleeding complications. Prothrombin time has been shown to increase by 8% to 11% when warfarin and rofecoxib interact. There is also an increased risk of gastrointestinal ulcerations and other bleeding complications when rofecoxib is used with aspirin. It should also be noted that rofecoxib is not a substitute for aspirin for cardiovascular prophylaxis.
 

SILDENAFIL

Sildenafil has been approved for the treatment of erectile dysfunction. Its mechanism of action involves a release of nitric oxide in the corpus cavernosum during sexual stimulation. Nitric oxide causes an increase in cyclic guanosine monophosphate (cGMP), which produces smooth muscle relaxation and the inflow of blood. Sildenafil does not directly cause relaxation but inhibits the degradation of cGMP by inhibiting phosphodiesterase type 5 (PDE5). It has no effect in the absence of sexual stimulation. Phosphodiesterase type 5 is also found in platelets, vascular and visceral smooth muscle, and skeletal muscle. By inhibiting PDE5, sildenafil decreases platelet aggregation and thrombus formation and enhances peripheral arterial-venous dilation.

Sildenafil is 4,000 times more selective for PDE5 than PDE3, which is related to control of cardiac contractility. It is 10 times more selective for PDE5 than PDE6, which is an enzyme in the retina that is related to an abnormality in color vision as a side effect.

Sildenafil is eliminated primarily by hepatic metabolism (via cytochrome P450) and is converted to an active metabolite, which is excreted primarily (80%) in feces and to a lesser degree (13%) in urine. Its terminal half-life is about four hours; it reaches its maximum concentration in 30 to 120 minutes. There is decreased clearance in the elderly, with a 40% greater concentration in men older than 65 to ages 18 to 45. There is no change in clearance in patients with mild to moderate renal insufficiency, but there is a 50% decrease in clearance in patients with severe renal impairment. There is also a significant decrease in clearance in patients who have hepatic cirrhosis.

Adverse reactions include headache, flushing, dyspepsia, nasal congestion, abnormal vision, diarrhea, dizziness, and rash. A transient dose-related impairment of color discrimination has been observed, without an effect on visual acuity, intraocular pressure, or papilledema. Priapism, or a prolonged erection of more than four hours, has been reported infrequently. However, the drug should be used with caution in patients with sickle cell anemia, multiple myeloma, and leukemia. A decrease in supine blood pressure of 5.5 to 8.4 mm Hg has been observed one to two hours after taking sildenafil.

Serious cardiovascular events, including myocardial infarction (MI), sudden cardiac death, ventricular arrhythmias, cerebrovascular hemorrhage, and transient ischemic attacks, have all been reported in patients who have taken sildenafil. It is not possible, however, to determine whether these events are related to the drug itself or to other factors, such as sexual activity, underlying cardiovascular disease, or other comorbid conditions. The safety of this drug is uncertain in patients who have had an MI, stroke, or life-threatening arrhythmia within the previous six months, and in patients with resting hypotension (90/50 mm Hg or lower) or hypertension (170/110 mm Hg or higher), congestive heart failure, coronary artery disease with unstable angina, or retinitis pigmentosa.

The most serious drug interactions with sildenafil involve the risk of these cardiovascular events. The drug is strictly contraindicated with the use of nitrates because of the risk of severe hypotension, which may lead to cardiovascular collapse. It is unknown when nitrates, if necessary, may be safely administered after a patient has taken sildenafil. Studies have shown that normal healthy individuals' plasma levels fall from 440 ng/ml at sildenafil's peak to 2 ng/ml at 24 hours. Patients older than 65, those with severe renal or hepatic impairment, and those who use cytochrome P450 inhibitors have a 24-hour plasma level three to eight times higher than normal controls. Even though their plasma levels would be much lower after 24 hours, it is still not clear whether it is safe to treat them with nitrates.

When sildenafil has been given with amlodipine, there have been documented drops in blood pressure (approximately 8 mm Hg). Sildenafil potentiates the antiaggregatory effect of sodium nitroprusside. There is no effect on bleeding time when it is given with aspirin, but there is an additive effect with concomitant heparin. Loop and potassium-sparing diuretics have been found to increase the active metabolite of sildenafil by 62%, and beta blockers increase it by 102%, although these increases seems to be of little clinical consequence.

Since cytochrome P450 enzymes metabolize sildenafil, other drugs that influence the activity of these enzymes will affect the sildenafil concentrations. Cimetidine has been shown to increase sildenafil concentrations by 56%, while erythromycin will increase it by 182%. Protease inhibitors such as saquinavir and ritonavir, taken by HIV-positive patients, will also increase concentration (by 140% and 300%, respectively). Rifampin, a cytochrome P450 inducer, will decrease sildenafil concentrations.

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