Trimethoprim toxicity

Trimethoprim- sulfamethoxazole Synergistic combination of folate antagonists blocks purine production and nucleic acid synthesis Bactericidal activity against susceptible bacteria Urinary tract infections Pneumocystis jiroveci pneumonia toxoplasmosis nocardiosis Oral, IV renal clearance (half-life 8 h) dosed every 8-12 h t formulated in a 5 1 ratio of sulfamethoxazole to trimethoprim Toxicity Rash, fever, bone marrow suppression, hyperkalemia... 

Folate metabolism Sulphonamides (also ) Trimethoprim Pyrimethamine Trimetrexate / Inhibit folate synthesis Inhibits dihydrofolate reductase Inhibits dihydrofolate reductase Inhibits dihydrofolate reductase Not present in mammalian cells Mammalian enzyme not inhibited Mammalian enzyme not inhibited Toxicity overcome with leucovorin... 

Phenytoin (Dilantin) [Anticenvulsant/Hydantoin] Uses Sz disorders Action X Sz spread in the motor cortex Dose Load Adults Peds. 15-20 mg/kg IV, 25 mg/min max or PO in 400-mg doses at 4-h intervals Maint Adults. Initial, 200 mg PO or IV bid or 300 mg hs then follow levels Peds. 4-7 mg/kg/24h PO or IV -s- daily-bid avoid PO susp (erratic absorption) Caution [D, +] Contra Heart block, sinus bradycardia Disp Caps, susp, inj SE Nystag-mus/ataxia early signs of tox gum hyperplasia w/ long-term use. IV BP, bradycardia, arrhythmias, phlebitis peripheral neuropathy, rash, blood dyscrasias, Stevens-Johnson synd Notes Levels Trough Just before next dose Therapeutic Peak 10-20 mcg/mL Toxic >20 mcg/mL phenytoin albumin bound, levels = bound free phenytoin w/ i albumin azotemia, low levels may be therapeutic (nl free levels) Interactions T Effects W/ amiodarone, allopurinol, chloramphenicol, disulfiram, INH, omeprazole, sulfonamides, quinolones, trimethoprim t... 

Trimethoprim is a competitive inhibitor of the enzyme dihydrofolate reductase and can thus prevent the formation of tetrahydrofolate thereby blocking the synthesis of purines. The affinity of trimethoprim for the enzyme in microorganisms is 10,000 times higher than for the human enzyme which explains the selective toxicity. Used alone its main indication is acute uncomplicated urinary tract infections. It is then as effective as co-trimoxazole but has the advantage of fewer adverse reactions. 

Serious adverse effects are rare except in AIDS patients. TMP-SMX can cause the same adverse effects as those associated with sulfonamide administration, including skin rashes, central nervous system (CNS) disturbances, and blood dyscrasias. Blood dyscrasias, hepatotoxicity, and skin rashes are particularly common in patients with AIDS. Most of the adverse effects of this combination are due to the sulfamethoxazole component. Trimethoprim may increase the hematological toxicity of sulfamethoxazole. Long-term use of trimethoprim in persons with borderline foUc acid deficiency, such as alcoholics and the malnourished, may result in megaloblastic anemia, thrombocytopenia, and granulocytopenia. 

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. 

Pentamidine is active against Pneumocystis carinii, trypanosomes, and leishmaniasis unresponsive to pentavalent antimonials. It is an alternative agent for the treatment of P. carinii pneumonia. Although it is more toxic than trimethoprim-sulfamethoxazole, it has been widely used in patients with acquired immunodeficiency syndrome (AIDS), in whom P. carinii infection is common. 

Pentamidine is a well-established alternative therapy for pulmonary and extrapulmonary disease caused by P jiroveci. The drug has somewhat lower efficacy and greater toxicity than trimethoprim-sulfamethoxazole. The standard dosage is 3 mg/kg/d intravenously for 21 days. Significant adverse reactions are common, and with multiple regimens now available to treat P jiroveci infection, pentamidine is best reserved for patients with severe disease who cannot tolerate or fail other drugs. 

The active form of folate is the tetrahydro-derivative that is formed through reduction by dihydrofolate reductase. This enzymatic reaction (Figure 29.5) is inhibited by trimethoprim, leading to a decrease in the folate coenzymes for purine, pyrimidine, and amino acid synthesis. Bacterial reductase has a much stronger affinity for trimethoprim than does the mammalian enzyme, which accounts for the drug s selective toxicity. [Note Examples of other folate reductase inhibitors include pyrimethamine, which is used with sulfonamides in parasitic infections (see p. 353), and methotrexate, which is used in cancer chemotherapy (see p. 378).]... 

Aminoglycosides are NOT indicated for the treatment of uncomplicated urinary tract infections these Infections respond to less toxic antimicrobial agents, such as trimethoprim-sulfamethoxazole. 

A 42-year-old woman developed symptoms of lithium toxicity and a raised serum concentration (2.1 mmol/1) while taking trimethoprim (616). 

The addition of trimethoprim caused severe lithium toxicity in a 40-year-old woman with a schizoaffective disorder following rehydration, she made a good recovery (729). 

PROCAINAMIDE ANTIBIOTICS - TRIMETHOPRIM Procainamide levels are t by trimethoprim Trimethoprim is a potent inhibitor of organic cation transport in the kidney, and elimination of procainamide is impaired Watch for signs of procainamide toxicity 1 the dose of procainamide, particularly in the elderly... 

DIGOXIN TRIMETHOPRIM, CO-TRIMOXAZOLE Trimethoprim may t plasma concentrations of digoxin, particularly in elderly people Uncertain postulated that trimethoprim 1 renal clearance of digoxin Monitor digoxin levels watch for digoxin toxicity... 

METHOTREXATE SULFAMETHOXAZOLE/ TRIMETHOPRIM t plasma concentrations of methotrexate and risk of toxic effects of methotrexate, e.g. myelosuppression, liver cirrhosis, pulmonary toxicity Sulfamethoxazole displaces methotrexate from plasma protein-binding sites and also 1 renal elimination of methotrexate. Trimethoprim inhibits dihydrofolate reductase, which leads to additive toxic effects of methotrexate Avoid concurrent use. If concurrent use is necessary, monitor clinically and biochemically for blood dyscrasias and liver, renal and pulmonary toxicity... 

TRIMETHOPRIM GANCICLOVIR/ VALGANCICLOVIR Possibly t adverse effects (e.g, myelosuppression) when trimethoprim is co administered with ganciclovir or valgancidovir Small t in bioavailability possible additive toxicity Well tolerated in a study. For patients at risk of additive toxicities, use only if benefits outweigh risks, and monitor FBC closely... 

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