Common anesthetic drugs

1. Many common anesthetic drugs may be affected by renal dysfunction owing to the changes that follow.

   1. Volume of distribution and electrolytes.

   2. pH (resulting in a higher percentage of nonionized drug).

   3. Decreased serum protein concentration resulting in increased bioavailability of protein-bound drugs, impaired biotransformation, and decreased rates of excretion (Table 5.5).

      
      TABLE 5.5 Pharmacologic Considerations for Perioperative Drugs Used in Patients With Chronic Renal Insufficiency

      Drug Class	Pharmacokinetics	Considerations
      Volatile anesthetics	Pulmonary metabolism	Sevoflurane produces compound A, a potentially nephrotoxic metabolite.
      Lipid Soluble
      Barbiturates	Free fraction of induction dose is almost doubled in patients with CKD.	May induce exaggerated hypotension and other clinical effects in CKD. Consider reducing induction dose
      Benzodiazepines	Increased free fraction in CKD	Potentiates clinical effects in CKD. Active metabolites accumulate with repeated dosing.
      Propofol	Rapid, extensive hepatic metabolism. Pharmacokinetics unchanged in CKD	Conflicting evidence on pharmacodynamics
      Etomidate	Increased free fraction in CKD	CKD may increase risk of toxic reactions
      Ketamine	Redistribution and hepatic metabolism largely responsible for termination of anesthetic effects. Minimal change in free fraction in CKD	CKD does not alter clinical effects.
      Opioids	Metabolized in liver	May have increased and prolonged effect in CKD. Active metabolites may prolong action with chronic administration: Morphine-6-glucoronide (morphine) has potent analgesic and sedative effects. Normeperidine (meperidine) has neurotoxic effects. Hydromorphone-3-glucoronide (hydromorphone) can cause cognitive dysfunction and myoclonus. Fentanyl has no active metabolite.
      Ionized Drugs
      Muscle relaxants	Standard dose of succinylcholine increases serum K+ by 0.5–0.8 mEq/L in CKD. Many nonpolarizing NMBs result in prolonged effects due to reliance on renal excretion	Succinylcholine is not contraindicated in CKD if serum K+ is not elevated. Cisatracurium, mivacurium, and rocuronium are preferable in CKD.
      Cholinesterase inhibitors	Decreased elimination in CKD, and half-life is prolonged	Half-life prolongation is similar to or greater than the duration of blockade from long-acting NMB so recurarization is rarely seen.
      Digoxin	Excreted in urine	Increased risk of toxicity in CKD.
      Vasoactive Drugs
      Catecholamines		Catecholamines with α-adrenergic effects constrict renal vasculature and may reduce renal blood flow.
      Sodium nitroprusside	Metabolized by the kidney and excreted as thiocyanate	Toxicity from thiocyanate accumulation is more likely in CKD.
      Antibiotics
      Penicillin, cephalosporins, aminoglycosides, and vancomycin	Predominately dependent on renal elimination	Loading dose is unchanged, but maintenance doses need adjustment.

   4. Loading doses do not need to be altered significantly in CKD as the duration of action of drugs administered by bolus is determined by redistribution, not elimination. With repeated dosing or long-term infusion, the duration of action is dependent on elimination, and maintenance doses of drugs with significant renal excretion should be reduced.

2. Lipid-soluble drugs are generally poorly ionized and must undergo metabolism by the liver to water-soluble forms before elimination by the kidney. With few exceptions, the metabolites have little biologic activity.

3. Benzodiazepines are metabolized in the liver to both active and inactive compounds, which are then eliminated by the kidney. Benzodiazepines are 90% to 95% protein bound. Great care must be taken in using diazepam because of its long half-life and its active metabolites. Accumulation of benzodiazepines and their metabolites may occur in severe renal failure. Benzodiazepines are not appreciably removed by dialysis.

4. Barbiturates, etomidate, and propofol are highly protein bound, and in hypoalbuminemic patients, a much greater proportion will theoretically be available to reach the receptor sites. Acidosis and changes in the blood–brain barrier may further reduce induction requirements. However, there is no high quality pharmacodynamic evidence for barbiturates and etomidate, and the studies on propofol have yielded conflicting results. Use clinical judgment.

5. Opioids are metabolized in the liver but may have a more intense and prolonged effect in patients with renal failure, particularly in hypoalbuminemic patients in whom protein binding will be reduced. Active metabolites of morphine and meperidine may prolong their actions, and accumulation of normeperidine may cause seizures. The pharmacokinetics of fentanyl, sufentanil, alfentanil, and remifentanil are unchanged in renal failure.

6. Ionized drugs. Drugs that are highly ionized at physiologic pH tend to be eliminated unchanged by the kidney, and their duration of action may be prolonged by renal dysfunction.

7. Depolarizing neuromuscular blockers (NMBs). Succinylcholine can be used safely in ESRD provided the potassium concentration is <5.5 mmol/L and repeated doses are avoided. An increase of ~0.5 mmol/L in serum potassium is observed both in ESRD and in healthy subjects.

8. Nondepolarizing NMBs. Traditionally, benzylisoquinolinium muscle relaxants (such as cisatracurium) are preferable in ESRD given their organ-independent metabolism. However, their metabolism is pH dependent, and acidosis in ESRD may prolong their effects. Rocuronium (an aminosteroid NMB) is excreted primarily in bile, and ~33% is excreted in urine resulting in prolonged action in renal failure. Sugammadex is a modified gamma-cyclodextrin that binds to and encapsulates aminosteroid neuromuscular blocking agents. Although it is excreted in urine, its efficacy as a reversal agent appears to be independent of excretion of the cyclodextrin-NMB complex. In ESRD, excretion of the cyclodextrin-NMB complex is prolonged but no evidence of recurarization has been reported in studies. No known adverse side effects of delayed excretion are known; however, more study in this area is warranted. Reassuringly, the cyclodextrin-NMB complex can be removed by dialysis.

   1. Cholinesterase inhibitors. With impaired renal function, elimination of the reversal drugs is decreased and their half-lives are prolonged.

   2. Digoxin is excreted in the urine, and patients with renal failure are at increased risk of digitalis toxicity.