Macrolides Cimetidine

Factors that may decrease theophylline clearance and lead to reduced dosage requirements include advanced age, bacterial or viral pneumonia, heart failure, liver dysfunction, hypoxemia from acute decompensation, and use of drugs such as cimetidine, macrolides, and fluoroquinolone antibiotics. 

CIMETIDINE MACROLIDES- ERYTHROMYCIN t efficacy and adverse effects of erythromycin, including hearing loss t bioavailability Consider an alternative antibiotic, e.g. clarithromycin. Deafness has been reversible with cessation of erythromycin... 

Most abundant isoform wide substrate range inhibited by cimetidine, macrolides, azoles, and ethanol (acute) induced by general P450 inducers such as carbamazepine, phenobarbital, phenytoin, and rifampin and by ethanol (chronic). 

Inducers (barbiturates, carbamezepine, rifampin) activity ° Inhibitors (cimetidine, macrolides, azole antifungals) —>T activity Protein C deficiency ... 

Carbamazepine levels are increased by CYP3A4 inhibitors (cimetidine, macrolides, diltiazem, fluoxetine, ketoconazole, verapamil, valproate) levels are decreased by CYP3A4 inducers (cisplatin, doxorubicin, felbamate, phenobarbital, phenytoin, primidone, rifampin, theophylline). Carbamazepine may increase levels of clomipramine, phenytoin, and primidone and lithium toxicity may decrease levels of phenytoin, warfarin, oral contraceptives, doxycycline, theophylline, haloperidol, alprazolam, clozapine, ethosuximide, and valproate may interfere with other anticonvulsants. 

Agents that may increase theophylline levels include allopurinol, beta blockers (nonselective), calcium channel blockers, cimetidine, oral contraceptives, corticosteroids, disulfiram, ephedrine, influenza virus vaccine, interferon, macrolides, mexiletine, quinolones, thiabendazole, thyroid hormones, carbamazepine, isoniazid, and loop diuretics. 

Drugs that may affect SSRIs Drugs that may affect SSRIs include azole antifungals, barbiturates, carbamazepine, cimetidine, cyproheptadine, lithium, macrolides,... 

Drugs that may affect benzodiazepines include alcohol/CNS depressants, cimetidine, oral contraceptives, disulfiram, isoniazid, probenecid, rifampin, smoking, theophyllines, and macrolides. 

Drugs that may affect tacrolimus include nephrotoxic agents (aminoglycosides, amphotericin B, cisplatin, cyclosporine), antifungals, bromocriptine, calcium channel blockers, cimetidine, clarithromycin, danazol, diltiazem, erythromycin, methylprednisolone, metoclopramide, carbamazepine, phenobarbital, phenytoin, rifamycins, cisapride, chloramphenicol, metronidazole, nefazodone, omeprazole, protease inhibitors, macrolide antibiotics, fosphenytoin, and St. John s wort. 

Citalopram (Celexa) [Antidepressant/SSRI] WARNING Closely monitor for worsening depression or emergence of suicidality, particularly in pts <24 y Uses Depression Action SSRI Dose Initial 20 mg/d, may t to 40 mg/d X in elderly hqjatic/renal insuff Caution [C, +/-] Hx of mania, Szs pts at risk for suicide Contra MAOI or w/in 14 d of MAOI use Disp Tabs, cap, soln SE Somnolence, insomnia, anxiety, xerostomia, diaphoresis, sexual dysfxn Notes May cause X Na /SIADH Interactions t Effects W/ azole antifungals, cimetidine, Li, macrolides, EtOH t effects OF BBs, carbamazepine, CNS drugs, warfarin X effects W/ carbamaz ine X effects OF phenytoin may cause fatal Rxn W/ MAOIs EMS Use caution w/ CNS depressants, may need a reduced dose concurrent EtOH... 

Quazepam (Doral) [C IV] [Sedative/Hypnotic/ Benzodiazepine] Uses Insomnia Action Benzodiazepine Dose 7.5-15 mg PO hs PRN i in elderly hqjatic failure Caution [X, /-] NA glaucoma Contra PRG, sleep apnea Disp Tabs SE Sedation, hangovCT, somnolence, resp depression Interactions T Effects W/ azole antifungals, cimetidine, digoxin, disulfiram, INH, levodopa, macrolides, neuroleptics, phenytoin, quinolones, SSRIs, verapamil, grapefruit juice, EtOH effects W/carbamazepine, rifampin, rifabutin, tobacco EMS Use caution w/ other benzodiazepines, antihistamines, opioids and verapamil, can T CNS depression concurrent EtOH and grapefruit juice use T CNS depression OD May cause profound CNS depression, confusion, bradycardia, hypotension, and altered reflexes flumazenil can be used as antidote activated charcoal may be effective... 

With the important exception of additive effects when combined with other CNS depressants, including alcohol, BZDs interact with very few drugs. Disulfiram (see the section The Alcoholic Patient in Chapter 14) and cimetidine may increase BZD blood levels, and diazepam may increase blood levels of digoxin and phenytoin. Antacids may reduce the clinical effects of clorazepate by hindering its biotransformation to desmethyidiazepam. Coadministration of a BZD and another drug known to induce seizures may possibly increase seizure risk, especially if the BZD is abruptly withdrawn. Furthermore, as noted earlier, important interactions have been reported among nefazodone, erythromycin, troleandomycin, and other macrolide antibiotics, as well as itraconazole. In each case, metabolism is inhibited, and triazolam levels can increase significantly. 

Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, nefazodone, loratadine, terfenadine, isoniazid, niacinamide, nicotinamide, propoxyphene, azoles (e.g., ketaconazole, itraconazole, and fluconazole), acetazolamide, verapamil, grapefruit juice, ... 

In contrast, decreases in theophylline metabolism by selective inhibitors of CYP1A2, such as fluvoxamine and some quinolone antibiotics, or by selective and potent inhibitors of CYP3A4, such as the macrolide antibiotics, have resulted in serious theophylline toxicity (22). It is postulated that taken over time, the macrolide antibiotics act as mechanism-based inhibitors of CYP isoforms other than just CYP3A4. Some nonselective inhibitors of P450s, such as cimetidine, some p-blockers and calcium channel blockers, and others (19,22), also appear to inhibit the metabolism of theophylline enough to cause toxicity. 

Macrolides, particularly erythromycin and clarithromycin, inhibit CYP3A4. With erythromycin, the inhibition of CYP3A4 is non-competitive due to irreversible binding with the isoenzyme to form an inactive complex. Thus, unlike the case with inhibitors with a short half-life (e.g. cimetidine), the offset of inhibition is slow since new enzyme must be synthesized to replace the inactive complexes. Azithromycin, clarithromycin and erythromycin can prolong the Q-T interval and must not be co-administered with other Q-T-prolonging drugs. 

Drug interactions Drugs utilizing the CYP2D6 (i.e., f luoxetine, cimetidine) or the CYP3A4 (i.e, macrolides, antiretrovirals) pathways may inhibit opioid metabolism and potentiate side effects. Drugs such as benzodiazepines and barbiturates should be used cautiously in combination with opioids, as they may potentiate respiratory depression or sedative effects. 

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