Cimetidine toxicity

Krenzelok EP, Litovitz P, Lippold KP, and McNelly CF (1987) Cimetidine toxicity An assessment of 881 cases. Annals of Emergency Medicine 16 1217-1221. 

FIGURE 8.20 Drugs as subsets of clinical profiles. While burimamide, cimetidine, and metiamide are all active histamine H2 antagonists with ulcer healing activity burimamide lacks a suitable toxicity and pharmacokinetic profile and cimetidine is adequately absorbed but still toxic. Only metiamide fulfills the requirements of a clinically useful drug. 

When carbamazepine is administered with primidone, decreased primidone levels and higher carbamazepine serum levels may result. Cimetidine administered with carbamazepine may result in an increase in plasma levels of carbamazepine that can lead to toxicity. Blood levels of lamotrigine increase when the agent is administered with valproic acid, requiring a lower dosage of lamotrigine... 

Use of die MAOIs must be discontinued 2 weeks before the administration of die SSRIs. When the SSRIs are administered witii die tricyclic antidepressants, tiiere is an increased risk of toxic effects and an increased tiierapeutic effect. When sertraline is administered witii a MAOI, a potentially fatal reaction can occur. Sjymptoms of a serious reaction include hyper-tiiermia, rigidity, autonomic instability witii fluctuating vital signs and agitation, delirium, and coma Sertraline blood levels are increased when administered witii cimetidine. 

The effects of buspirone are decreased when the drug is administered with fluoxetine Increased serum levels of buspirone occur if the drug is taken with erythromycin or itraconazole Should any of these combinations be required, the dosage of buspirone is decreased to 2.5 mg BID, and the patient is monitored closely. Venlafaxine blood levels increase with a risk of toxicity when administered witii MAOIs or cimetidine There is an increased risk of toxicity when trazodone is administered with the phenothiazines and decreased effectiveness of trazodone when it is administered with carbamazepine Increased serum digoxin levels have occurred when digoxin is administered with trazodone There is a risk for increased phenytoin levels when phenytoin is administered witii trazodone... 

When two antiarrhythmic dragp are administered concurrently the patient may experience additive effects and is at increased risk for drug toxicity. When quinidine and procainamide are administered with digitalis, tiie risk of digitalis toxicity is increased. Hiarmacologic effects of procainamide may be increased when procainamide is administered with quinidine When quinidine is administered with the barbiturates or cimetidine, quinidine serum levels may be increased. When quinidine is administered with verapamil, there is an increased risk of hypotensive effects. When quinidine is administered with disopyramide, there is an increased risk of increased disopyramide blood levels and/or decreased serum quinidine levels. 

Cimetidine, an H2 antagonist used therapeutically in patients with ulcers, inhibits activity of hepatic microsomal enzymes. When rats or mice were pretreated with cimetidine, dose-related lethality of methyl parathion was reduced, and cholinergic signs of toxicity were delayed. Simultaneous administration with methyl parathion did not reduce toxicity (Joshi and Thornburg 1986). 

Certain medications (e.g., cimetidine, diltiazem, erythromycin, fluoxetine, fluvoxamine, isoniazid, itraconazole, ketoconazole, nefazodone, propoxyphene, and verapamil) added to carbamazepine therapy may cause carbamazepine toxicity. 

This lack of complete effectiveness led to the hypothesis that a second type of histamine receptor existed. In 1972, Black et al. (55) discovered a new series of antagonists which they called H2 receptor blockers. Burimamide was the first highly effective H2 blocker, but it was poorly absorbed orally. The modified compound, metiamide, had better absorption but was found to cause granulocytopenia (57.58). Finally, cimetidine was tested and found to be a potent and relatively non-toxic antagonist (59). Cimetidine is now widely used clinically to treat duodenal ulcers, Zollinger-Ellison Syndrome and other gastric hypersecretory diseases (32). 

Il.b.l.1. Adverse effects of anti-secretory treatment. Histamine H2 antagonists and proton pump inhibitors are very safe as well as effective treatments. Cimetidine has small effects on hepatic drug metabolism which are only of clinical signiflcance with drugs used in doses close to toxic levels, notably phenytoin, aminophylline and warfarin. Other adverse effects such as headache, rash and thrombocytopenia are rare. 

The inherent anticholinergic properties of procainamide may interfere with the therapeutic effect of cholinergic agents. Patients receiving cimetidine and procainamide may exhibit signs of procainamide toxicity, as cimetidine inhibits the metabolism of procainamide. Simultaneous... 

In patients whose condition has been stabilized by flecainide, the addition of cimetidine may reduce the rate of flecainide s hepatic metabolism, increasing the potential for toxicity. Flecainide may increase digoxin concentrations on concurrent administration. 

Several drug interactions involving amantadine and rimantadine are clinically significant. Anticholinergic drugs can potentiate the toxicity of amantadine. Thiazide-triamterene, trimethoprim-sulfamethoxazole, quinine, and quinidine increase plasma amantadine levels. Cimetidine decreases rimantadine clearance, and aspirin and acetaminophen decrease rimantadine plasma levels. 

Cimetidine Inhibition of metabolism at CYP2D6 isoenzyme Sudden TCA toxicity No coadministration Henauer and Hollister, 1984... 

Lignocaine Cimetidine, propranolol Increased risk of lignocaine toxicity. 

Cottrell, S., Oliver, K., Lake, B.G. Powell, C.J. (1996) Strain-specific enhancement or inhibition of coumarin hepatotoxicity in mice following pretreatment with two different liver enzyme-inducing agents. Fundam. appl. Toxicol, 34, 47-55 Cox, D., O Kennedy, R. Thornes, R.D. (1989) The rarity of liver toxicity inpatients treated with coumarin (1,2-benzopyrone). Hum. exp. Toxicol, 8, 501-506 Dexeus, E.H., Logothetis, C.J., Sella, A., Fitz, K., Amato, R., Reuben, J.M. Dozier, N. (1990) Phase II study of coumarin and cimetidine in patients with metastatic renal cell carcinoma. J. din. Oncol, 8, 325-329... 

Szymanski S, Lieberman JA, Picou D, et al. A case report of cimetidine-induced clozapine toxicity. J Clin Psychiatry 1991 52 21-22. 

In patients with heart failure, lidocaine s volume of distribution and total body clearance may both be decreased. Thus, both loading and maintenance doses should be decreased. Since these effects counterbalance each other, the half-life may not be increased as much as predicted from clearance changes alone. In patients with liver disease, plasma clearance is markedly reduced and the volume of distribution is often increased the elimination half-life in such cases may be increased threefold or more. In liver disease, the maintenance dose should be decreased, but usual loading doses can be given. Elimination half-life determines the time to steady state. Thus, although steady-state concentrations may be achieved in 8-10 hours in normal patients and patients with heart failure, 24-36 hours may be required in those with liver disease. Drugs that decrease liver blood flow (eg, propranolol, cimetidine) reduce lidocaine clearance and so increase the risk of toxicity unless infusion rates are decreased. With infusions lasting more than 24 hours, clearance falls and plasma concentrations rise. Renal disease has no major effect on lidocaine disposition. 

Metronidazole has been reported to potentiate the anticoagulant effect of coumarin-type anticoagulants. Phenytoin and phenobarbital may accelerate elimination of the drug, whereas cimetidine may decrease plasma clearance. Lithium toxicity may occur when the drug is used with metronidazole. 

Isosteric replacement of the thiourea moiety with the cyanoguanidine moiety gave cimetidine (39), a potent H2-receptor antagonist that lacks the toxicity of 38. Cimet-idine is a widely used anti-ulcer medication because of its effectiveness in treating ulcers and relative safety. It is noteworthy that in this example, this isosteric modification selectively reduced toxicity without affecting pharmacological activity. 

---