Clinically significant drug interactions with antituberculosis agents

Clinically Significant Drug Interactions with Antituberculosis Agents

ELSEVIER

Shannon M. Lee, PharmD and Mark Bunker, PhannD PSYCHOPHARMACY

Pharmacology

Update

CENTER

AND

PROFESSIONAL

RESIDENT,

(S.M.L.)

UNIVERSITY

OF

SERVICE

ASSOCIATE

WESTERN

MISSOURI, (M.B.),

Abstract

Introduction

Tuberculosis (TB) has, until recently, been considered to be primarily of historical importance in the United States, butinthepast1Oyeursthenumberof reprtdcuse.9hasied. AS a result of mismanaged patients and poor treutment outcomes, a strain of Mycobacterium tuberculosis resistant to both of the most e$cct;ve antitubwlar agents, isoniazid {A?@ and rifampin has emetged and necessitates the use of mm-e toxic and less e&ectice drugs fm longer period% of time. compounding the problem is the treatment of HlV/ AIDS patients with TB, which also requires several medications during treatment (1,2). Psychiatric populations are at gtwter risk fm developing TB, and are o+ treated with multiple medkatiomthat~thepotentialto~act adversely with antitubercular agents. Bifampin is a weUknown potent indhcer of both cytochrome P45O (CW) 2C and CW3A and has the majority of clinically signifiant drug interactions. lA?H inhibits the metabolism of many drugs due to a mechun~ other than CYP enzyme inoolt.Lhlginhractiom inoolving these and other ant& tuWr drugs cam result in either therapeutic failure or toxicity of antitubercular and/or psychxmctive agents. AdditionaRypsychosi.shasoccurred,aL though rarely, as a direct result of the use of antitubercular treatment in TB ptknts uxth no history of psychiatric symptoms (3). Preoention of these draginduced ~~CWW emmts as well as education and me* compliance are essential fadots in the optimal treatment of psychiatric patients with comorbid TB. 0 1997 Else&r Science

Tuberculosis (TB) has, until recently, been considered to be primarily of historical importance in the United States. Reported casesdecreased by 5.6% per year between 1953 and 1984 (from more than 84,000 casesto 22,255 cases). From 1985 to 1993, however, reported cases of TB increased by 14% (up to 25,313 cases).The United States Centers for DiseaseControl (CDC) estimates that about 4% of the general population is infected with TB and that over a lifetime, 10% of those will develop active TB disease. Factors contributing to its re-emergence include the human immunodeficiency virus (HIV) epidemic, migration from countries where TB is common, and increasesin concentrated living environments such as homeless shelters and nursing homes (1). As a result of mismanaged patients and poor treatment outcomes, a strain of Mycobacterium tuberculosis that is resistant to both of the most effective antitubercular agents, isoniazid (INH) and rifampin, has emerged. This multi-drug resistant strain necessitatesuse of more toxic and lesseffective drugs for longer periods of time. Compounding the problem is the treatment of HIV and acquired immunodeficiency syndrome (AIDS) patients with TB caused by Mycobacterium avium-intracellulare complex (MAC), which requires several medications during treatment. Many of the medications used in these regimens have potential for significant drug interactions with psychoactive agents (I,2). Additionally, psychosiscan occur as a direct result of the use of antitubercular treatment in TB patients with no history of psychiatric symptoms (3).

kc.

MELMCAL

UPDATE

FOR PSYCHlAlRlSTS

2;4:107-113,1997.

8 1997 EImev18r 9cience ls9N 1093~7979~97#l7.00 PII 9m93-7979mw9353

Inc.

Address reprint requests to: Shannon M. Lee, PharmD, Western Missouri Mental Health Center, 600 East 22nd Street, Kansas City, MO 64108.

MISSOURI

KANSAS

CITY,

SAN

ANTONIO,

MENTAL MISSOURI

HEALTH AND

SOLVAY

TEXAS

The mentally ill incur a higher risk of developing TB as many are homeless, have low incomes, abuse substances, have poor accessto health care, an&or are malnourished. Psychiatric populations are at greater risk for developing TB, and are often treated with multiple medications that have the potential to interact adversely with antitubercular agents. As reported by Takeda and colleagues (4), hospital stays for patients with both schizophrenia and TB were significantly longer than schizophrenic patients without TB. The mean length of stay for schizophrenic patients with TB was 1701.3 days versus 491.6 days for men and 579.2 days for women without TB. Drug interactions resulting in toxicity of medications with narrow therapeutic indices and in psychiatric decompensationare possible,therefore, it is important for clinicians to be aware of how patients taking psychoactive medications can be impacted by antitubercular agents.

Tuberculosis

Transmission

Tuberculosis is caused by Mycobacterium tuberculosis and occurs most often by inhalation of tiny air-borne particles expelled from persons with active pulmonary or laryngeal TB. Particles can remain suspendedin the air for several hours. The tiny droplets enter the alveoli, multiply, and enter the lymph nodes with the potential to spread through the blood to other tissuesand organs of the body. The most common site of infection are the lungs; 15% of cases are extrapulmonary and commonly include the kidneys, brain, and bone. Between 10 and 15 million people in the U.S. are currently infected with M. tuberculosis. If the immune system is intact, those who are infected do not develop active disease,remain asymptomatic, and are not contagious. Risk of active diseaseis considerably higher in patients who are immunocompromised (e.g., HIV/AIDS,

S. M. Lee and

LM.

Bunker

MEDICAL

Hodgkin’s disease, immunocompromising drugs). TB patients also diagnosed as HIV-positive carry a risk for disease development 100 times greater than those with TB infection alone (1). In order to reduce the risk of transmission, persons with infectious TB require isolation and the immediate initiation of antitubercular therapy. The most common pulmonary TB symptoms are productive cough, chest pain, and hemoptysis. Systemically, symptoms include fatigue, night sweats, chills, weight loss, and/or fever (1,s).

Screening Infection

for TB Disease

and

Screening is necessary in high-risk populations to ident+ persons already infected with TB in need of prophylaxis and those who have active disease needing treatment. The CDC considers high-risk populations to include persons with or at risk for HIV infection; close contacts of persons with infectious TB; persons who inject drugs; foreign-born persons from areas where TB is common (i.e., Asia, Africa, Latin America); medically underserved, low-income populations; long-term care facility residents; and the homeless. Persons with certain medical conditions may also be at higher risk, including those with recent infection with M. tuberculosis, diabetes mellitus, silicosis, low body weight (10% below ideal), cancer of the head and neck, hematologic and reticuloendothelial diseases, end-stage renal disease, intestinal bypass or gastrectomy, chronic malabsorption ST”dromes, prolonged immunosuppressive therapy, and chest radiograph findings suggestive of previous TB. Health care workers and staff of long-term care facilities should be tested upon employment and thereafter as determined by the risk of transmission in that facility (1). The Mantoux test is the recommended tubercular skin test. An intradermal injection of 0.1 ml of purified protein derivative (PPD) tuberculin containing 5 tuberculin units is given. The test should be read 48 to 72 hours after injection and any palpable swelling measured and recorded in millimeters. A reaction of 5 mm or larger is considered a positive result in HIV-infected patients, close contacts of a person with TB, persons with chest radiograph find-

ings suggestive of TB, and persons who inject drugs and who have an unknown HIV status. In persons with known risk factors, a reaction of 10 mm or larger is positive. In persons with no known risk factors, a reaction of 15 mm or greater is considered positive. The Mantoux test is not 100% accurate and there is a possibility of a false-positive or -negative result. False-positive results can occur in nontuberculous mycobacterial infection or in those with a history of vaccination with bacille CalmetteGuerin (1,5). The lack of a reaction does not rule out TB disease or infection. About 10 to 25% of persons with TB disease have no reaction to the tubercular skin test. Anergy is a condition that occurs in immunocompromised persons during which the delayed hypersensitivity reaction is either smaller or absent. Factors contributing to anergy include HIV infection, military TB, severe illness, viral infections, Hodgkin’s disease, and administration of immunocompromising drugs. Even though infected with M. tuberculosis, about one-third of patients with HIV infection and greater than 60% of patients with AIDS may have skin test reactions of less than 5 mm. Anere can be detected by administering at least two other delayed-type hypersensitivity tests using the Mantoux method. If there is a reaction greater than 3 mm to any of the antigens, anergy is not present (1).

TB Prevention

and Treatment

Persons with a positive skin test and who are in one of the aforementioned high-risk populations should be treated with preventive therapy regardless of age. Persons younger than 35 years of age with no known risk factors and a skin test reaction of greater than I5 mm should be considered for preventive therapy. Persons who may have occupational exposure to TB (e.g., staff of nursing homes, drug treatment centers, correctional facilities) should also be considered for preventive therapy if they have a positive tuberculin reaction. Caution is advised in giving INH preventative therapy to those over 35 years of age unless they are at high risk, because the risk of hepatitis outweighs the benefits. Clinical trials have shown that risk for TB disease is decreased by more than 90% in infected persons complet-

UPDATE

FOR PSYCHIATRISTS

ing a full 12-month course of daily INH. Patients should be assessed monthly for adverse reactions and compliance. Refer to the I994 edition of the “Core Curriculum on TB” by the CDC for further guidelines addressing close contacts with TB patients, pregnant patients, and infants (1). INH competitively inhibits p,yridoxine and can cause peripheral neuropathy. Pyridoxine (B,) 6 to 50 mg/day can be given for prevention or relief of peripheral neuropathy and should be taken daily by patients at greatest risk, including patients taking greater than 6 mg/kg/day of INH, alcoholics, diabetics, children, and malnourished patients (1,6). The current standard regimen for preventative treatment is 300 mg INH daily in adults for at least six months or 10 to 15 mg/kg body weight in children continued for at least nine months. If the patient is likely to be INH-resistant, rifampin is recommended for six months in doses of 450 mg/day in adults weighing less than 50 kg or 600 mg/day in adults weighing 50 kg or more. Children should receive rifampin 20 mg/kg up to a maximum of 600 mg/day for nine months. For patients with both INH and rifampin-resistant TB, observation alone should be considered; however, for those at especially high risk, treatment may include either six months of ethambutol and pyrazinamide or pymzinamide and one of the quinolones (ciprofloxacin or ofloxacin). There are several alternative regimens being used including a directlv observed, twice weekly regimen of i5 mg/ kg/dose. A new short-course preventive therapy is being evaluated using rifampin and pyrazinamide for 2 months and rifampin alone for 4 months (1,6,7). A minimum of four drugs are needed for initial treatment of active TB. The usual regimen is INH, rifampin, pyra zinamide, and either ethambutol or streptomycin. Upon receipt of drug susceptibility reports, the drug regimen can be adjusted and continued for 6 to 24 months. A single drug should never be added to a failing drug regimen as resistance can easily develop. In the event of multi-drug resistance or concurrent AIDS, the quinolones (e.g., ciprofloxacin) and thiacetazone are the most common additions. The goal is to provide the safest and most effective treatment in the shortest amount of time using susceptible agents. Insuring

MEDICAL

Table

UPDATE

FOR PSYCHIATRISTS

1. Cytochrome

Drug Interactions

P450 Enzymes Affected by Antituberculars

and Psychotropics.

CYPlA2

Substrates

Clozapine, fluvoxamine, 3” amine TCAs (amitriptyline, imipramine, clomipramine), Tacrine, caffeine

3” TCAs, citalopram, diazepam, phenytoin, NSAIDs, hexobarbital, propranolol

Inhibitors

Fluvoxamine, pefloxacin

Fluvoxamine, fluoxetine, and sertraline, ketoconazole

Inducers

Smoking

compliance to the treatment regimen is perhaps one of the most important factors. If treatment is not continued for a sufficient length of time, some tubercle bacilli may survive and the patient can become ill again with resistance. If treated adequately, most patients have a good prognosis (1).

Mechanisms

of Drug Interactions

Clinically significant drug interactions may lead to drug toxicity or a reduced therapeutic benefit. Drug interactions can be classified as either pharmacodynamic or pharmacokinetic in nature. Genetics and ethnicity can affect the potential for drug interactions (e.g., the rate of acetylation or change in cytochrome P45O isoenzyme concentration) as can age and gender. Pharmacodynamic interactions occur between drugs with related pharmacologic actions, leading to a combined effect that is either greater (additive, synergistic) or less (antagonistic) than would be expected with either drug alone. The more difficult to predict interactions are pharmacokinetic in nature and involve changes in absorption, distribution, metabolism, and/or excretion of one or more of the medications in the regimen. These changes can affect the blood concentration, therefore affecting the intensity and/or duration of drug action (73). The most important pharmacokinetic interactions with antitubercular drugs are a result of changes in the metabolism of one or more drugs. The CYP system, located in the endoplasmic reticulum, includes at least 30 isoenzymes that are involved in the oxidative me-

cYP2c9/19

enoxacin,

Rifampin

tabolism of many different types of drugs including most of the psychoactive medications (see Table 1 for the CYP enzymes affected by antitubercular and psychoactive medications). Recent characterization of specific isoenzymes has allowed the prediction and therefore avoidance of potential drug interactions involving the CYP system. Medications metabolized by one or more of the CYP enzymes are considered substrates. Drugs can also act as inducers or inhibitors of the specific enzymes (7,8,9). Induction, by increasing the metabolic activity of the CYP system, can affect substrates by resulting in faster clearance, shorter half-life, and decreased therapeutic effect. Metabolite formation may increase and, depending on the activity of the metabolites, a greater or lesser response can result. Drugs that can induce certain CYP classes include rifampin, isoniazid, carbamazepine, phenobarbital, phenytoin, and glucocor-ticoids. Cigarette smoking is also a common inducer. Inhibition or antagonism of metabolism of certain CYP enzymes occurs by compounds such as cimetidine, fluvoxamine, ketoconazole, ciprofloxaxin, co-trimoxazole, haloperidol (CYP2D6), amitriptyline (CYP2D6), macrolides, and selective serotonin reuptake inhibitors (SSRIs). Inhibition of CYP enzymes can either cause levels of unmetabolized active drug to accumulate, possibly causing toxicity, or can prevent the conversion of an inactive prodrug to its active metabolite, resulting in pharmacologic failure (7,9,10). Rates of elimination from the body can be altered, because competition for

109

Agents

(7,8,9,10)

Action

ciprofloxacin,

with Antituberculosis

CYP3A Alprazolam, clonazepam, carbamazepine, diazepam, midazolam, sertraline, triazolam, 3” amine TCAs, protease inhibitors Erythromycin Fluoxetine, fluvoxamine, nefazadone, norfluoxetine, sertraline Clarithromycin, erythromycin, azithromycin, troleandomycin, protease inhibitors, azole antifungals Carbamazepine, pheny*oin, phenobarbital Rifampin, rifabutin

carrier systems may change renal clearance. Chelation, antacids, or ion-binding resins may alter the absorption and distribution of drugs, and INH can be affected to a clinically significant extent by coadministration with antacids. In addition, drugs are bound to plasma proteins to varying extents. It is the free or unbound fraction of drug that is available to act either therapeutically or toxically. Displacement of drug from protein-binding sites causes an increase in the free or unbound fraction, which initially could cause an increase in effect and subsequently could cause a decrease in effect as more drug is eliminated from the body (7).

Clinically Significant lnteractlons

Drug

Isoniazid is metabolized primarily by acetylation to a number of inactive metabolites. Genetically, patients may be rapid or slow acetylators. Slow acetylators tend to have greater risk of drug interactions than rapid acetylators. INH inhibits CYP2El but, because this is not an enzyme commonly involved in the metabolism of many drugs, clinically significant drug interactions are few. However, substrates of 2E1, ethanol, and acetaminophen serum concentrations can be elevated by INH (10). INH inhibits the metabolism of many drugs due to a mechanism other than CYP enzyme involvement. Table 2 shows clinically significant drug interactions with INH. In the neuropsychiatric patient population, problems can arise due to drug interactions with INH. The combination of INH and disulfuram has caused

S. hf. Lee and M. Bunker

Table

2. Clinically

MEDICAL

Significant Drug Interactions

Acetaminophen

Cycloserine

Theophylline

(Tegretolm)

(Seromycin@)

CXS toxicity of both drngs CNS effects due to both drugs

(DilantW)

4

(Theo-Dura)

* Effect

w

Glucocorticoids (Prednisone, Insulin (Humulin@, NPH)

t 4

central

nwv~us

system:

INH,

Dexamethasone)

of acetaminophen

Monitor for signs of toxicity, serum level, adjust dose as necessary Monitor for signs of CNS toxicity including dizziness and drowsiness Avoid concomitant use unless absolutely necessary, monitor for CNS changes Monitor for signs of toxicity, serum level, adjust dose as necessary Monitor signs of toxicity, serum level, may need several weeks for full effect

on Isoniazid

Antacids (e.g., Mylanta@), Maalox@)

CNS.

Management

Limit consumption (hepatofoxicity) 4

Disulfuram Phenytoin

on Drug

(Tylenol@)

Carbamazepine

FOR PSYCHIATRISTS

with Isoniazid.(‘i,ll) Effect

Drug

UPDATE

Give INH 2 hours before or 6 hours after, monitor for reduced INH response Monitor for reduced INH or enhanced steroid effects Monitor for enhanced INH side effects

isoniazid.

changes in affect and behavior as well as in coordination through a proposed mechanism of inhibition of dopamine metabolism. This combination should be avoided whenever possible, but if not possible, patients should be monitored closely for signs of central nervous system (CNS) toxicity. Although clinical significance is unknown, diazepam and triazolam therapy should be monitored for prolonged sedative effect when given concomitantly with INH. INH can inhibit the metabolism of the anticonvulsants phenytoin and carbamazepine to a clinically significant extent causing elevated concentrations and potential toxicity. Anticonvulsant dose reductions may be needed and should be based on serum concentrations. In addition, reports indicate primidone metabolism has been inhibited and in a slow acetylator valproic acid levels increased significantly during concomitant INH therapy; monitoring for this potential is suggested (7,ll). INH has some ability to inhibit monoamine oxidase. Reports have shown an interaction between INH and tyramine-containing foods (e.g., wine and cheese), resulting in a hypertensive crisis of flushing, headache, and palpitations as seen with inhibitors monoamine oxidase (MAOIS). It is also known that serotonergic antidepressants, including SSRIs and tricyclic antidepressants (TCAS) in combination with MAOIs can cause a serotonin syndrome man-

ifested by excitation, diaphoresis, hyperthermia, myoclonus, rigidity, and hypertension. Clinicians should be aware of the possibility of the interaction between INH and SSRIs, TCAs, and MAOIs because isolated cases have been reported. However, cases of patients taking the combination with no problem have also been documented. Although not an absolute contraindication, signs and symptoms of serotonin syndrome and hypertensive crisis should be watched for when using these drugs concomitantly. The package insert for the newly released combination product of INH, rifampin, and pyrazinamide warns patients to avoid tyramine-containing foods (7,12,13). Rifampin is a well-known potent inducer of both CYPBC and CYP3A and has many clinically significant drug interactions, some of which include psychoactive agents. When given in corn& nation with drugs metabolized by these enzymes, the potential result is either toxicity or pharmacologic failure as the rate of metabolism is increased (8). Table 3 shows clinically significant drug interactions with rifampin. Women should be warned of the risk of failure of oral contraceptive agents with concurrent rifampin therapy, because interaction occurs with both the estrogen and progesterone components (6). Although there are no reports in the literature, theoretically this interaction could also occur with Depo-Provera or

110

Norplant contraceptive agents. Patients should be educated on the need for alternative nonpharmacologic contraception. Clinically significant neuropsychiatric drug interactions with rifampin, probably due to enzyme induction, include nortriptyline and other tricyclic antidepressants, diazepam, beta-blockers (e.g., propranolol, metaprolol), and phenytoin. The addition of rifampin to phenytoin may cause increased seizure activity because of enhanced phenytoin metabolism. As a result, whenever an antitubercular agent is added to an antiepileptic regimen, a serum concentration should be assessed four half-lives after the addition (7). Previous reports in the literature of rifampin decreasing serum concentrations of haloperidol (HDL) have raised concerns about causing decompensation in psychiatric patients. Kim and associates (4) divided 12 schizophrenic patients into two groups, group I included 7 patients who were healthy and who had not had TB for the previous 2 years, and group II included 5 patients who had been receiving antitubercular medications for more than 9 months and were about to terminate treatment as they had been cured of TB. Mean daily trough concentrations of HDL in group I declined rapidly after initiation of rifampin, reaching a minimum level in about 7 days. The HDL level was 62.8% of baseline at day 3,

MEDICAL

Table

UPDATE

FOR PSYCHIATRISTS

3. Clinically

Significant

Drug

Drug

Interactions

Effect DT!c

with

Rifampin.

Glucocorticoids Prednisone Dexamethasone Immunosuppressive Azathioprine (Imurans) Cyclosporine (Sandimmune@) Oral Contraceptives Sulfonylureas Tolbutamide (Orinase@) Chloramphenicol (Chloromycetin@) Phenytoin (Dilantin@) Theophylline (Theo-DuP)

with

Antituberculosis

Agents

heart

failure,

dose

(7,11,14,X)

on Management

Dwt

Anticoagulants Warfarin (CoumadinQ) Antifungals Fluconazole (Diflucanm) Ketoconazole (Nizoral@) Cardioactive Digitoxin (Crystodigin@) Digoxin (Warfarina) Quinidine (Duraquin@) Disopyramide (Norpace@) Propafenone Nifedipine (Procardia@) Diltiazem (CardizemB) Metoprolol ( Lopressora) Propranolol (Inderala) Centrally active Diazepam (Valium@) Haloperidol (Haldola) Methadone

Interactions

Increase

dose

by 2- to S-fold,

Separate

doses

Monitor serum necessary Monitor serum Monitor Monitor Monitor Increase Increase

monitor

prothrombin

by 12 h, monitor

for infection,

digitoxin/digoxin

levels,

quinidine

time

serum

monitor

levels

for arrhythmias,

increase

if

levels

propafenone serum response, increase response, increase dose if necessary, dose if necessary,

levels dose, consider alternative dose, consider alternative monitor for therapeutic monitor for therapeutic

response response

t Increase dose Increase dose by 50%, monitor for psychosis and Increase dose to control symptoms of withdrawal, methadone

Haldol levels caution when

DC

rifampin

while

on

t

t w

Increase

dose

by 2- to S-fold

Increase

dose,

monitor

Alternative Increase

contraception methods should be used, document counsel dose based on blood sugar control and at DC of rifampin

Monitor

serum

level,

increase

Monitor Monitor

serum serum

levels levels

esp. on start or stop of rifampin, for efficacy and toxicity, titrate

Monitor

for

for

transplant

rejection,

serum

levels

dose titrate dose

dose

Effect on Rifampin Co-trimoxazole

(Bactrim@)

4

increased

adverse

effects

and hepatoxicity

DC, discontinuing.

37.4% at day 7, and 30% at day 28. In II, daily trough HDL levels increased after the discontinuation of rifampin and reached the maximum level (9.3 to 22.5 @ml) at the 14th day. The trough was 140.7% of baseline at day 3, 228.7% at dav 7, and 329% at dav 28 after discontinuation. Four of the 12 patients (including 3 dropout patients) showed a return of previous psychotic symptoms. A new steady-state concentration was reached 7 to 10 days after the addition or discontinuation of rifampin to HDL. It is important to monitor for decompensation when rifampin is added to existing haloperidol or other aforementioned neuropsychiatric therapy. When rifampin is discontinued from the regimen, one should monitor for increased serum concentrations of group

existing medications and the possibility of toxicity; dosage adjustments may be required. Factors that determine the time required to reach a new steady state after the addition of an enzyme-inducing agent include the elimination half-lives of both the drug and the inducing agent along with the degradation rate of the enzyme. Time to steady state and time to elimination of drug after discontinuation is typically five half-lives. Animal studies have shown that the degradation of CYP protein is a first-order process with a half-life of 8 to 30 hours similar to the half-life of haloperidol. Therefore, an expected time period to steady state or complete degradation of the CYP enzyme would be approximately 40 to 150 hours (2 to 6 days). Rifampin has been reported to have a

111

plasma half-life of 5 hours (4). Half-lives should be taken into account when predicting changes in serum concentrations of interacting drugs.

Other Antitubercular Interactions

Drug

The antitubercular agents pyrazinamide and etionamide can increase concentrations of INH and potentially increase the risk for INH-induced hepatotoxicit>‘. Pyrazinamide can decrease concentrations

of rifampin

however

the

clinical

significance is not known. The bioavailability of ethambutol is reduced when aluminum hydroxide is given concomitantly and therefore should be separated

(1,7).

by

2 hours

between

medications

S. M. Lee and IZI. Bunker

Table

4. Clinically

MEDICAL

Significant

Drug

Interactions

with

Effect on Drug

(Theo-DuP, norfloxacin,

Slobid@) or periloxacin

Beta-blockers

(metaprolol,

propranolol)

Cyclosporine (Sandimmune@) norfloxacin Diazepam (Valium@) Fenbufen (NSAID)

with

Management

4

Choose quinolone with less potential, lomefloxacin, ofloxacin, rufloxacin, with others, monitor serum levels

4

Monitor for bradycardia, heart failure, atrioventricular conduction Monitor for impaired renal function

ciprofloxacin,

ciprofloxacin,

-a& ?

Phenytoin

(Dilantin@)

4

Warfarin

(Coumadinm)

? Effect on Quinolone

Antacids Cimetidine

(Mylanta@, Maalox@) (Tagamet@)

Ranitidine (Zantac?) Didanosine (Videx@, DDI) Iron Supplements (Feosol@) Sucralfate (Carafate@)

w 6

(contains

Al and

is no longer one of the short-course treatment for TB because it must be given by injection, but it is used in multi-drug resistance. Because it is ototoxic and nephrotoxic, it should not be given in combination with other aminoglycosides, cephalosporins, vancomycin, amphotericn B, cyclosporin, or cisplatin because toxicity can be potentiated. Neuromuscular blocking drug effects can also be increased by streptomycin. Thioacetazone can rarely cause ototoxicity and should be used with caution in combination with streptomycin (7). In contrast to first-line agents such as rifampin, the quinolones are potent inhibitors of cytochrome enzyme systems (see Table 4 for clinically significant drug interactions with the quinolone antibiotics). Ciprofloxacin, enoxacin, and perfloxacin are potent inhibitors of CYPlA2 (refer to Table 1 for neuropsychiatric drugs affected by this enzyme). Ofloxacin does not effect this enzyme and is mainly eliminated unchanged in the urine. Psychiatric patients taking proprano101 or metaprolol should be monitored for bradycardia, heart failure, or prolonged atrioventricular conduction when taken in combination with a quinStreptomycin mainstays of

FOR PSYCHIK~RISTS

Quinolones.(7,11)

Dw Aminophylline Theophylline enoxacin,

UPDATE

for increased sedation have occurred; caution NSAIDs for toxicity or reduced

in those effect

prone

when

to seizures

stopped,

when

serum

for hypoprothrombinemia

olone, because inhibition of metabolism could occur. Diazepam and phenytoin concentrations may increase in combination with ciprofloxacin, enoxacin, norfloxacin, and perfloxacin due to inhibition of metabolism and patients should be monitored for prolonged side effects as well as signs and symptoms of toxicity. Patients taking phenytoin should be monitored for toxicity upon initiation of one of the aforementioned quinolones and for seizure activity upon discontinuation; serum concentrations and dosage adjustments may be needed (11).

Emergent

and prolonged

Monitor for therapeutic failure Monitor for inhibition of theophylline cont. when given with quinolone Monitor for reduced benefit Give quinolone 2 h before and monitor response Give quinolone 2 h before iron or give IV and monitor Avoid if possible or administer several h before or 6 h after and monitor

t t t t

Mg)

Monitor Seizures using Monitor levels Monitor

i.e., fleroxacin, flosaquinan, spafioxacin, temafloxacin; and signs of toxicity

Psychosis

Psychosis has been reported to have developed as a direct result of antitubercular medications in TB patients with no history of psychosis. The drug most often implicated is isoniazid and there are at least 10 reported cases (3). Most patients had no previous psychiatric history and manifested a sudden, marked change in mental status 3 days to 2 months after initiation of INH. Symptoms most often included bizarre delusions and visual hallucinations. Generally, the psychosis has been reversible upon discontinuation of INH and the TB was

112

treated with an alternative agent. Two possible mechanisms have been proposed for this drug-induced phenomenon. The first being the monoamine oxidase inhibition of INH. The second possibility is vitamin B, deficiency causing decreased metabolism of tyrosine and tryptophan to dopamine, norepinephrine, and serotonin. Although a very rare reaction, individuals who are taking more than 5 mg/kg INH daily; who are more than 50 years old; who have concomitant disease states, including diabetes mellitus, hepatic insufficiency, alcoholism, and hyperthyroidism; or who have psychiatric history may be at increased risk (3). Tuberculosis cases have been increasing over the last 10 years and are becoming more difficult to treat as multi-drug resistant strains are emerging. Psychiatric patients are at increased risk of contracting the disease and therefore will need both preventive and active therapy. Due to the clinically significant drug interactions caused by many of the antitubercular agents, patients on psychoactive medications are at risk for toxic serum drug levels and/or psychiatric decompensation. Additionally, antitubercu-

MIWICAI. UWATE

FOR PSYCHIATRISTS

lar medications, specifically isoniazid, have been implicated in emergent psychosis in non-mentally ill patients. Prevention of these drug-induced adverse events is vital in an already difficult-to-treat population of TB patients. Education, prevention, and medication compliance are essential factors in the optimal treatment of psychiatric patients with comorbid TB.

Drug Interactions

4.

5.

6.

References 1. US Department of Health and Human Services and Centers for Disease Control and Prevention. Core Curriculum on Tuberculosis: What the Clinician Should Know. Atlanta: Public Health Services: 1994. 2. ASHP Therapeutic Position Statement on Strategies for Preventing and Treating Multidrug Resistant Tuberculosis. Am J He&h-Syst Pharvn 1997;54:42831. 3. Pallone KA, Goldman MP, Fuller MA. Isoniasid-associated psychosis: Case re-

7.

8. 9.

port and review of the literature. Ann Pharvnacother 1993;27:167-70. Kim Y, Cha I, Shim J, et al. Effect of rifampin on the plasma concentration and the clinical effect of haloperidol concomitantly administered to schizophrenic patients. / CZin Psychopharvrmcd 1996;16:247-52. Jo HS. Assessment and management of persons coinfected with tuberculosis and human immunodeficiency virus. Nurse Practitioner 1993;18( 11):42-g. Ward ES Jr. Tuberculosis. In: Young LY and Koda-Kimble MA (eds). Appkx~ Therapeutim Vancouver: Applied Therapeutics, Inc., 199*5, 59-159-15. Grange JM, Winstanley PA, Davies P. Clinically significant drug interactions with antituberculosis agents. Drug Sufetfj 1994;11(4):24%51. Ciummo PE, Katz NL. Interactions and drug-metabolizing enzymes. American Phannmy 199.5;NS35(9):41-51. Nemeroff CB, DeVane CL,, Pollock BG. Newer antidepressants and the cyto-

113

10.

11. 12.

13.

14. 15.

with Antituberculosis

Agents

chrome P450 system. Am J Psychiatv~~ 1996;153:311-20. Ketter TA, Flockhart DA, Post R&I, et al. The emerging role of cytochrome P450 3A in psychopharmacology. J Clin P.sycho?lharv,lacoZ 1995;15:38798. Hansten PD, Horn JR (eds). Drug Interactions: Analysis und Management. USA: Applied Therapeutics, Inc., 1997. Malek-Ahmadi P, Chavez M, Contreras SA. Coadministration of isoniazid and antidepressant drugs [letter]. 1 Clin PsychiatrrJ 1996;57(11):550. Evans ME, Kortas KJ. Potential interaction between isoniazid and selective serotonin-reuptake inhibitors [letter]. Am ] Health-Syst Phann 1995;.52: 2135-6. . Venkatesan K. Pharmacokinetic drug interactions with rifampicin. C/in Pharvnacokinet 1992;22( 1):47-65. Borcherding SM, Baciewicz AM, Self TH. Update on rifampin drug interactions II. Arch Intern Mrd 1992;152: 711-6.