Cimetidine interaction with other drugs

The metabolism of lorazepam (e.g., Ativan), oxazepam (e.g., Serax), and temazepam (e.g., Restoril) are not likely to be affected, and one of these agents may be preferred when a benzodiazepine is indicated in a patient being treated with cimetidine. The experience with ranitidine (e.g., Zantac), famotidine (Pepcid), and nizatidine (Axid) suggests that these agents are not likely to inhibit hepatic enzyme systems, and these other histamine H2-receptor antagonists are less likely than cimetidine to interact with other drugs that are metabolized via these pathways. 

Drug interactions Cimetidine is a CYP450 inhibitor and can inhibit the metabolism of phenytoin, warfarin, and theophylline. Famotidine, nizatidine, and ranitidine are unlikely to cause clinically significant drug interactions. All antagonists have the potential to interact with other drugs that require gastric acid for absorption (e.g., ketoconazole, itraconazole). 

Memantine is predicted to interact with other drugs that use the same renal cationic transport system leading to increased levels of memantine and/or the other drug. The manufacturer lists cimetidine, ranitidine, hydrochlorothiazide, metformin, procainamide, qninidine, qninine and triamterene as possible examples. However, in an interaction study, the concurrent use of memantine and hydrochlorothiazide/triamterene did not result in any change in the steady-state AUC of memantine or triamterene, and the AUC of hydrochlorothiazide showed a modest reduction of about 20%. This degree of change is unlikely to be clinically relevant. Therefore, whether any clinically important interactions occur via this mechanism remains to be established. 

Biguanides This class of antidiabetics may cause acute poisoning with adverse effects such as acidosis and may be treated by supportive therapy. These drugs have therapeutic interactions with other antidiabetic drugs, alcohol, drugs that affect kidney function, and cimetidine. 

Interactions. Involvement of protease inhibitors with the cytochrome P450 system provides scope for interaction with numerous substances. Agents that induce P450 enzymes (e.g. rifampicin, St John s wort) accelerate their metabolism, and reduce plasma concentration enzyme inhibitors (e.g. ketoconazole, cimetidine) raise their plasma concentration competition with other drugs for the cytochrome enzymes can lead to variable results. Ritonavir is itself a powerful inhibitor of CYP 3A4 and CYP 2D6. This effect is utilised when ritonavir in small quantity is combined (in capsules) with lopinavir to inhibit its metabolism and increase its therapeutic efficacy. The present account should be sufficient to warn the physician, and thereby the patient, to take particular heed when seeking to co-administer any drug a with protease inhibitor. 

Pharmacokinetics. Carbamazepine is extensively metabolised one of the main products, an epoxide (a chemically reactive form), has anticonvulsant activity similar to that of the parent drug but may also cause some of its adverse effects. The t) of carbamazepine falls from 35 h to 20 h over the first few weeks of therapy due to induction of hepatic enzymes that metabolise it as well as other drugs, including corticosteroids (adrenal and contraceptive), theophylline and warfarin. Cimetidine and valproate inhibit its metabolism. There are complex interactions with other antiepilepsy drugs, which constitute a reason for monodrug therapy. 

A single 800-mg dose of metronidazole was given to 12 healthy subjects following 9 days of treatment with diosmin 500 mg daily. The metronidazole AUC and maximum plasma concentrations were raised by 27% and 25%, respectively. This interaction is thought to occur because of an inhibitory effect of diosmin on metronidazole metabolism by hepatic enzymes, and inhibition of P-glycoprotein. The increase in metronidazole levels is similar to that seen with other drugs (e.g. cimetidine (above)) that are not considered to be clinically significant. Therefore no clinically... 

In a pharmacokinetic study, 10 elderly women with breast cancer were given anastrozole 1 mg daily for 10 weeks and 5 of them who also had hypertension were additionally given quinapril, after week 4, for 28 days. Quinapril did not affect plasma anastrozole levels and dose modification is not required during concurrent use. A clinical study with cimetidine has shown that it does not affect the pharmacokinetics of anastrozole, which suggests that anastrozole is unlikely to be affeeted by other drugs that inhibit cytochrome P450. Another clinical study showed that anastrozole does not affect the pharmacokinetics of antipyrine (phenazone), so that it is unlikely to interact with those drugs which are known to be affected by enzyme inducers and inhibitors. 

Information appears to be limited to this report but it is consistent with the way cimetidine interacts with many other drugs. Ranitidine, and possibly other H2-receptor antagonists such as famotidine or nizatidine, which do not inhibit liver enzymes, would seem to be preferable and safer alternatives however, this needs confirmation. 

Probenecid markedly increased the AUC of the active metabolite of oseltamivir, but because of the large safety margin of oseltamivir, this increase is not considered to be clinically relevant. " Oseltamivir did not alter amoxicillin pharmacokinetics, and is therefore unlikely to interact with other renally secreted organic acids. Other drugs that are involved in the active anionic tubular secretion mechanism are also unlikely to interact. Cimetidine does not interact with oseltamivir, and other drugs that are inhibitors of the renal cationic secretion transport process are unlikely to interact. ... 

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. 

There are drug products whose interaction with PVC bags and infusion sets are so high that they must include labehng precautions for use with PVC containers. These drugs include antineoplastics such as pachtaxel, docetaxel, tacrolimus, and teniposide, and others such as ciprofloxacin, cefoperazone sodium, fluconazole, metronidazole HC1, cimetidine, and propofol [64,65]. 

Drugs metabolized by CYP that interact with cimetidine include, but are not limited to, the following lidocaine, quinidine, midazolam, triazolam, nifedipine, verapamil, and fentanyl (4). In each instance, inhibition of CYP by cimetidine results in reduced metabolic clearance and increases in serum concentrations of the other drug, which can lead to the expected toxicity and adverse experiences characteristic of the other drug. 

A retrospective analysis of 3995 patients treated with azithromycin did not show any pharmacokinetic interactions in patients who were also taking various other drugs, including cimetidine (1,45). 

The many drug interactions described with cimetidine are largely attributable to inhibition of CYP isozymes or renal clearance of other drugs. Cimetidine also reduces hepatic blood flow and so can, for example, reduce the clearance of lidocaine. In the kidneys cimetidine interferes with the tubular excretion of procainamide and quinidine. Both effects are small, and the long list of drugs for which interference is demonstrable (Table 1) is out of all proportion to the number for which interference is of chnical significance. 

The overall safety record of the currently marketed agents, particularly cimetidine and ranitidine, which have had extensive worldwide use, is excellent, and in practice safety issues seldom affect drug choice (1), except perhaps when it is necessary to avoid interactions with phenytoin, theophylline, or warfarin. Surveillance studies, which have been going on for a quarter of a century (including 10-year studies in many patients, mainly involving cimetidine and ranitidine), have failed to detect any serious adverse effects other than those recognized by 1980, or any adverse effect on mortality (2). 

Reversible inhibitors, such as cimetidine, which interact with the complexed iron at the active site of the enzyme to inhibit oxidation of other drugs. The inhibition occurs before any oxidation of the inhibitor occurs and is reversible once the inhibitor is removed. 

Lamivudine inhibits the intracellular phosphorylation of zalcitabine and antagonizes zalcitabine s antiretroviral activity in vitro, although the clinical significance of this interaction is unknown. Probenecid increases the zalcitabine AUC by about 50%, probably through inhibition of tubular secretion cimetidine increases the AUC by 36% via an unknown mechanism. Zalcitabine should be avoided in patients with a history of pancreatitis or neuropathy because the risk and severity of both complications increase. Coadministration of other drugs that cause pancreatitis or neuropathy also will increase the risk and severity of these symptoms. Ethambutol, isoniazid, vincristine, cisplatin, and pentamidine, as well as the antiretroviral drugs didanosine and stavudine, therefore, should be avoided. 

Interactions with the following drugs may increase the risk of hypoglycemia other hypoglycemics, sulfonamides, propranolol, salicylates, clofibrate, probenecid, pentamidine, valproic acid, dicumarol, cimetidine, MAO inhibitors, and alcohol. In addition, co-ingestion of alcohol may occasionally produce a disulfiram-like interaction (see p 186). 

On theoretical grounds the manufacturers contraindicate the concurrent use of sibutramine with MAOIs, and they say that it should not be given with serotonei ic drugs because of the risk of the serious serotonin syndrome. The manufacturers say that the use of sibutramine with other centrally acting appetite suppressants is contraindicated and they caution the use of cold and flu remedies. No clinically relevant interactions have been seen between sibutramine and cimetidine, and no interaction occurs with oral contraceptives. 

Drug interactions barbiturates, tranquilizers, other narcotics, antihistamines, antidepressants, MAO inhibitors, and alcohol can all increase CNS depression. The risk of bradycardia and hypotension increases for patients on beta blockers and calcium channel blockers. Cimetidine, used to treat peptic ulcers, interacts with sufentanil and increases the risk of respiratory depression. 

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