Accumulation, drug

From the mechanistic point of view three basic principles of microbial resistance to drugs are known inactivation of the drug, alteration of the target, and reduced drug accumulation at the target site. However, several variations on these themes are known. 

Fhtients with liver or kidney disease are usually given dragp with caution because a cumulative effect may occur. When the patient is unable to excrete the drug at a normal rate the drug accumulates in the body, causing atoxic reaction. Sometimes, the primary health care provider lowers the dose of the drug to prevent a toxic drug reaction. 

Monitor serum creatinine because patients with renal insufficiency (CrCl less than 50 mL/minute) may have reduced ribavirin elimination resulting in increased drug accumulation and toxicity (e.g., hemolytic anemia). 

Kawakami, M., Kagotani, K., Okumura, K., Akiyama, S., Kuwano, M., A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation, Cancer Res. 1996, 56, 4124-4129. 

The SSRIs, with the possible exception of citalopram and sertraline, may have a nonlinear pattern of drug accumulation with chronic dosing. 

The benzodiazepines that have been most commonly marketed as sedative-hypnotics include temazepam (Restoril), estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), and triazolam (Halcion). Of these five, temazepam is the most easily metabolized and eliminated. Therefore, temazepam is preferred for elderly and medically ill patients to minimize the risk of drug accumulation. 

Impaired liver function, either due to primary disease or secondary to cardiac failure, may cause drug accumulation (Tl). Renal insufficiency may have two effects changes in the binding properties of plasma protein secondary to uremia can occur (R6, SI 6), or the drug and its metabolites may accumulate owing to impaired urinary excretion. 

Metabolism/Excretion - About 50% is excreted in the urine as the unchanged drug and 30% as metabolites (20% mono-N-dealkyIdisopyramide [MND]). The plasma concentration of MND is approximately one-tenth that of disopyramide. The mean plasma half-life is 6.7 hours (range, 4 to 10 hours). In impaired renal function, half-life values ranged from 8 to 18 hours. Therefore, decrease the dose in renal failure to avoid drug accumulation. 

Steady-state oxybutynin plasma concentrations are achieved by day 3 of repeated oxybutynin ER dosing, with no observed drug accumulation or change in oxybutynin and desethyloxybutynin pharmacokinetic parameters. 

Hepatic function impairment In patients with preexisting severe liver disease, hepatic encephalopathy (manifested by tremors, confusion, and coma, and increased jaundice) may occur. Because amiloride is not metabolized by the liver, drug accumulation is not anticipated in patients with hepatic dysfunction, but accumulation can occur if hepatorenal syndrome develops. 

Renal/Hepatic function impairment Use with caution and in reduced doses in patients with hepatic impairment metabolism may be impaired, leading to drug accumulation. Use with caution in patients with significantly impaired renal function. Elderly Be cautious in dose selection for an elderly patient, usually starting at the low end of the dosing range. Elderly patients may be sensitive to the anticholinergic side effects of TCAs. 

Renal function impairment Data in end-stage renal failure patients repeatedly treated with zolpidem did not demonstrate drug accumulation or alterations in pharmacokinetic parameters. No dosage adjustment in renally impaired patients is required however, closely monitor these patients. 

Renai impairment - Adjust dosage according to Ccr rates to prevent drug accumulation. 

Renal function impairment WnWe caution should be used in patients with severe renal failure, therapeutic concentrations of nalidixic acid in the urine, without increased toxicity caused by drug accumulation in the blood, have been observed in patients on full dosage with creatinine clearances (Ccr) as low as 2 to 8 mL/min. Special risk Use nalidixic acid with caution in patients with epilepsy, liver disease, or severe cerebral arteriosclerosis. 

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