02.04.2.3 Renal Insufficiency

In renal insufficiency, (e.g in neonates, and with age-related renal impairment), the duration of action of drugs excreted unchanged from the kidney is prolonged. Examples of drugs excreted unchanged by the kidney include the aminoglycoside antibiotics and digoxin. The levels of these drugs may increase in renal insufficiency and produce toxicity. Both of these drugs have a small therapeutic window, which means that the concentrations that cause toxicity effects are only slightly above the concentrations that cause a therapeutic effect. The toxicity with aminoglycosides includes ototoxicity (ringing in ears to deafness). Digoxin is used to increase the force of the heart beat in heart failure, and has a small therapeutic window, with toxicity including cardiac arrhythmias. When renal excretion is impaired, it may be necessary to decrease the dose of these drugs and/or increase the dose interval.

Clearance is term given to the combination of metabolism and excretion of a drug. When a drug is metabolised by the liver and the metabolite is excreted via thekidney, renal insufficiency can lead to increased plasma concentrations and adverse effects. Thus, we need to lower doses when there is kidney insufficiency. But how do we know when there is renal insufficiency? We assess kidney function.

Kidney function is assessed from the creatinine clearance. Creatinine clearance is the removal of creatinine from the body. Creatinine is natural metabolite of creatine (found in muscle). The properties that make creatinine ideal for assessing kidney function are that creatinine has a steady level in the blood and is freely filtered by the kidney. Thus, with normal function, the plasma and urine levels of creatinine will be similar. In kidney insufficiency plasma creatinine levels are increased, and urine levels are decreased.

When creatinine clearance is inhibited, this indicates renal insufficiency, and that it may be necessary to decrease the dose of drug to avoid toxicity. This can occur with morphine in renal insufficiency. An important metabolite of morphine is morphine-6-glucuronide, which has similar pharmacological actions to morphine. Morphine-6-glucuronide is excreted from kidney. In renal insufficiency, morphine-6-glucuronide builds up and increases efficacy (pain relief). Unfortunately, increased levels of morphine-6-glucuronide also lead to an increased likelihood of adverse effects, such as respiratory depression. In elderly patients, lower doses of morphine are used partly to compensate for loss of kidney function.