Lithium creatinine clearance

Patients at increased risk of NSAID-induced gastrointestinal adverse effects (e.g., dyspepsia, peptic ulcer formation, and bleeding) include the elderly, those with peptic ulcer disease, coagulopathy, and patients receiving high doses of concurrent corticosteroids. Nephrotoxicity is more common in the elderly, patients with creatinine clearance values less than 50 mL/minute, and those with volume depletion or on diuretic therapy. NSAIDs should be used with caution in patients with reduced cardiac output due to sodium retention and in patients receiving antihypertensives, warfarin, and lithium. 

At one time, sustained-release preparations were thought to reduce renal toxicity, but more recent evidence has cast doubt on this assumption ( 313). A patient on long-term maintenance lithium should have renal function monitored periodically (i.e., every 12 months) with a urinalysis, BUN, and creatinine. If abnormal, a more intensive evaluation should include 24-hour urine osmolality and creatinine clearance. It is advisable to reduce maintenance lithium to optimal minimal dose-blood levels and, if possible, to avoid concomitant antipsychotics, which may enhance toxicity. Some data support the use of a once-a-day dose schedule to minimize peak lithium concentrations over a 24-hour period (314). 

Ionized lithium is readily absorbed from the gastrointestinal tract and is excreted almost entirely by the kidney, which ordinarily clears it at a rate of about one-quarter to that of creatinine clearance (53). 

In a comparison of patients taking long-term lithium (n = 10) or short-term lithium (n = 9) and bipolar patients not taking lithium (n = 10), there was significantly lower creatinine clearance and renal concentrating ability in the long-term group (372). 

Chronic renal insufficiency (creatinine clearance under 80 ml/minute), for which there was no apparent alternative explanation, developed in 53 patients taking long-term lithium (mean 17.7 years) 7 required periodic dialysis (375). 

A 48-year-old man taking lithium and chlorprothixene had a creatinine clearance of 60 ml/minute and a renal biopsy showing chronic interstitial nephritis (380). 

These include mesalazine, metformin, NSAIDs, tetracyclines (except doxycycline and minocycline), chloramphenicol, lithium, methotrexate, chloroquine, fibrates, chlorpropamide and glibenclamide, Clinically, it is useful to measure urine output per hour or per 24 hours as a fall in urine output in the presence of adequate fluid intake often indicates or warns of some impairment of renal function. Furthermore, it is neither expensive nor time-consuming to perform a quick test for albumin, casts and red cells in the urine, and to measure pH. Creatinine clearance values are often used to determine the safe doses for several drugs (e.g. NSAIDs, ciclosporin). 

Elimination. Renal blood flow, glomerular filtration and tubular secretion decrease with age above 55 years, a decline that is not signalled by raised serum creatinine concentration because production of this metabolite is diminished by the age-associated diminution of muscle mass. Indeed, in the elderly, serum creatinine may be within the concentration range for normal young adults even when the creatinine clearance is 50 ml/min (compared to 127 ml/min in adult male). Particular risk of adverse effects arises with drugs that are eliminated mainly by the kidney and that have a small therapeutic ratio, e.g. aminoglycosides, chlorpropamide, digoxin, lithium. 

Figure 4. Evolution of estimated creatinine clearance over time in 35 patients on lithium therapy. Each line denotes the evolution in one patient up for more than 1 year. (Reproduced with permission from Presne eta [142]).

Clinical effects of lithium are slow in onset and may not be apparent before a week or two of daily treatment. Lithium is cleared exclusively by the kidney at a rate 20% of that of creatinine. Clearance is influenced by many factors, including renal function, serum sodium concentration, hydration state, pregnancy, and the presence of other drugs. High urinary levels of sodium inhibit renal tubular reabsorption of lithium, thus decreasing its plasma levels. By decreasing blood volume, thiazides may increase lithium plasma levels. Any drug that can cross the blood-brain barrier can cross the placental barrier The answer is (C). 

A 74-year-old man with treatment-refractory bipolar disorder and multiple medical problems, including chronic renal insufficiency (creatinine clearance 26 ml/minute) secondary to type 2 diabetes and lithium, took psychotropic... 

Monitoring therapy One of the predictors of lithium clearance, and consequently lithium toxicity, is creatinine clearance [89 ], and lithium concentrations are closely associated with its adverse effects. In a study of 186 patients who were followed between 1973 and 2000 (an average of 5.7 years/patient) in which nine specific adverse effects were recorded monthly in a standardized manner (diarrhea, nausea, vomiting, stomach ache, tiredness, concentration deficits, tremor, polyuria, and polydipsia), the frequency of adverse effects increased as a function of lithium concentration as did their intensity [90. The mean number of adverse effects increased from 3.3 at a concentration of 0.6 mmol/1 to 3.8 in patients with a concentration of 1.2 mmol/1. However, there was also a relation between mood state and adverse effects. Patients with manic symptoms had fewer adverse effects (an average of 2.0),... 

Excretion Virtually entirely in urine. Lithium clearance about 20% of creatinine. Plasma half-life about 20 hours. 

Various NSAIDs, such as ibuprofen, indomethacin, ketoprofen, phenylbutazone, piroxicam, and oxyphenbutazone, can decrease renal creatinine and lithium clearance by their common inhibitory action on prostaglandin synthesis. Aspirin (acetylsalicylic acid) and sulindac have not been found to increase lithium plasma steady-state concentrations. ... 

---