Page 1761 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

1230 PART 11: Special Problems in Critical Care

TABLE 125-4 Effects of Liver Dysfunction on Drug Disposition and Effect TABLE 125-6 Selected Drugs That Have Active Metabolites Requiring Renal Excretion
Bioavailability Drug Metabolite
Drugs that undergo extensive first-pass metabolism may have a significantly higher oral Acebutolol N-Acetylacebutolol
bioavailability in cirrhotics than in normal subjects. Impaired drug absorption because of Allopurinol Oxypurinol
bowel wall edema has not been found in studies of cirrhotic subjects. GI hypomotility may
delay peak response to enterally administered drugs in these patients. Atracurium Laudanosine
Protein binding Azathioprine Mercaptopurine
Hypoalbuminemia or altered glycoprotein levels may significantly affect the fractional Cimetidine Cimetidine sulfoxide
protein binding of acidic or basic drugs, respectively. Monitoring of free drug levels may Cyclophosphamide 4-Hydroxycyclophosphamide, others
be indicated. In addition, drug-drug interactions by displacement from plasma protein Digitoxin Digoxin
binding sites may become important when biotransformation is concomitantly impaired.
Disopyramide Mono-N-desisopropyldisopyramide (MND)
Volume of distribution
Flecainide Meta-O-dealkylflecainide
Altered plasma protein concentrations may affect the extent of tissue distribution of drugs
which are normally highly protein bound. The presence of significant edema and ascites Hydroxyzine Cetirizine
may alter the Vd of highly water-soluble agents (eg, aminoglycosides). Ifosfamide 4-Hydroxyifosfamide, others
Biotransformation Meperidine Normeperidine
The presence of cirrhosis may result in some decrease in drug clearance, though not predict- Metoprolol α-Hydroxymetoprolol
ably so. Specific information regarding use of each agent prescribed in patients with a type Morphine Morphine-6-glucuronide
and severity of liver disease similar to the patient in question should be sought, if possible.
Nitroprusside Thiocyanate
Excretion
Pancuronium 3-OH-pancuronium
Renal elimination of drug or metabolites may be impaired by concomitant renal
insufficiency, which may be unsuspected based on a “inappropriately” low serum Procainamide N-Acetyl-procainamide (NAPA)
creatinine in patients with severe liver disease. Propafenone 5-Hydroxypropafenone
Pharmacodynamic effects Propoxyphene Norpropoxyphene
Sedative effects (and side effects ) of drugs may be augmented in patients with liver disease. Sulfonamides Acetyl- metabolites
Tolbutamide Hydroxy- and carboxy-tolbutamide
clearance by extracorporeal devices, see Chap. 124; as a general rule, Vecuronium 3-Desacetylvecuronium
an increase in drug clearance by 30% or more is regarded as sig- Data from Brater DC. Dosing regimens in renal disease. In: Jacobson HE, Striker GA, Klahr S, eds.
nificant. Dialyzability by hemodialysis (HD) or peritoneal dialysis is The Principles and Practice of Nephrology. 2nd ed. St. Louis, Mosby-Year Book; 1995.
suggested by water solubility, low molecular weight (<500 Da; up to
20000 Da with high-flux membranes), low protein binding (<90%), hemofiltration, or continuous venovenous hemofiltration) may be
small volume of distribution (Vd <1 L/kg), and a low intrinsic clear- achieved by either transmembrane sieving (convection) or membrane
ance (<500 mL/70 kg per minute). HD clearance is additionally drug adsorption (eg, it requires 20 mg of aminoglycosides such as
3,20
affected by the porosity and surface area of the membrane used, and gentamicin or tobramycin, which are polycationic, to saturate each
the blood pump and dialysate flow rates. Drug clearance by hemo- new AN69 hemofilter, which is anionic); the addition of diffusive
filtration (slow continuous ultrafiltration, continuous arteriovenous clearance by use of countercurrent dialysate flow (continuous arte-
riovenous hemodiafiltration or continuous venovenous hemodiafil-
TABLE 125-5 Effects of Congestive Heart Failure (CHF) on Drug Disposition and Effect tration) augments small-solute clearance (since the capacity of these
substances to cross the membrane is limited by the concentration
Bioavailability
gradient, not particle size). Data regarding altered drug disposition
Impaired drug absorption because of bowel wall edema. Passive hepatic congestion may alter (changes in Vd or clearance) induced by extracorporeal membrane
first-pass metabolism. Peripheral edema inhibits absorption of nonintravenous parenteral routes. oxygenation (ECMO) or plasmapheresis are available only for agents
Protein binding that have been specifically studied (eg, aminoglycosides, opiates, and
phenytoin), and in the case of ECMO, studies have been performed
Protein amount and function is altered to the extent that renal and liver function is almost exclusively in pediatric patient populations. The impact of HD
compromised with circulatory failure. In addition, competitive binding of plasma proteins is not strictly limited to dialysis clearance. Recent findings suggest
may occur with common CHF therapy agents (eg, furosemide).
that the nonrenal clearance of some agents is altered by HD. A study
Volume of distribution of midazolam in subjects with end-stage renal disease implicated
The presence significant edema and pulmonary edema may alter the Vd of highly transporters (human organic anion-transporting polypeptide and/or
water-soluble agents (eg, aminoglycosides). intestinal P-glycoprotein) as the likely drug disposition bottleneck in
Biotransformation uremia rather than CYP3A4. 20
Hypoperfusion of liver may alter drug metabolizing enzyme function, especially with ■ RENAL EXCRETION
flow-dependent drugs (eg, lidocaine). Renal clearance of drugs or metabolites is usually achieved by glomerular
Excretion filtration, and diminished clearance owing to renal insufficiency is there-
Renal elimination is decreased to extent that renal and liver functions are compromised by fore proportional, caused by a decline of GFR. Renal blood flow (RBF)
circulatory dysfunction; hepatic elimination is limited in flow-dependent drugs (eg, lidocaine). averages approximately 1300 mL/min, which is about 20% to 25% of car-
Pharmacodynamic effects diac output. Renal plasma flow (RPF, 650 mL/min) is about 50% of RBF,
and 20% of RPF undergoes glomerular filtration, so that GFR averages
Increased sensitivity to negative inotropes at therapeutic doses. Increased arrhythmic potential 130 mL/min. The remaining 80% of RPF circulates in peritubular capil-
with antiarrhythmic drugs. Patients with CHF are more prone to contrast nephropathy. laries, where constituents may be secreted into or reabsorbed from renal

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