Cardiovascular Disorders

Acute decreases in cardiac output diminish organ blood flow and may impair drug clearance. Absorption of orally administered drugs may also be decreased in patients with congestive heart failure.

Hepatic Dysfunction

Disorders of the liver can impact hepatic metabolism of medications differently depending on the type and degree of dysfunction. In general, patients with hepatic disease have a decreased clearance of medications that are hepatically metabolized, with those that undergo hepatic oxidation more severely impaired than those that undergo hepatic conjugation. Patients with hepatic disorders are commonly hypoalbuminemic and may also have increased volumes of distributions of highly protein bound drugs (because of the increased distribution of free drugs in all body fluids, including ascetic fluid). In hypovolemic patients, perfusion of the liver may be compromised, resulting in decreased drug clearance. Drugs that undergo extensive enterohepatic recirculation may also have increased oral bioavailability because of the decreased hepatic metabolism. Generally, hepatic metabolism of drugs is decreased to a greater extent in patients with more severe hepatic dysfunction.

Renal Dysfunction

Although low-molecular-weight drugs (that are not highly protein bound) are filtered at the glomerulus and then partially reabsorbed, most drugs eliminated by the kidney are secreted. The dose or interval of drugs eliminated renally by either mechanism must be changed when renal function is impaired. Renal clearance of medications decreases in proportion to decreases in creatinine clearance (CrCl).

Dialysis

Whether a drug is affected by hemodialysis depends on the drug’s physicochemical properties and the method of hemodialysis. In general, highly water-soluble drugs are more dialyzable than are water-insoluble drugs. Drugs with large molecular weights, large volumes of distribution (>2 L/kg), and extensive protein binding are not removed by conventional intermittent hemodialysis with low flux filters; however, high-flux dialysis may remove larger molecules. Currently, the majority of patients receive hemodialysis with high-flux filters. In addition to the physiochemical properties of a medication, the amount of drug removed by hemodialysis depends on the length of the hemodialysis session, the rate of blood flow, and dialysate. Patients receiving ultrafiltration will have lower percentages of drug removal than those receiving hemodialysis. If a medication is significantly removed by hemodialysis, patients may require a supplemental dose following the dialysis session. Continuous renal replacement therapy uses membranes that are similar to high-flux filters and approximates a CrCl of 30 to 60 mL/min depending on rate of blood flow and dialysate (Chapter 20). Medications in these patients should be adjusted accordingly.

Fluid Status Changes

Hypovolemia concentrates extracellular solutes, including drugs, and may reduce renal drug clearance. In addition, hypovolemia and shock decrease hepatic blood flow, which, in turn, reduces hepatic drug metabolism. In contrast, fluid overload lowers plasma drug concentrations, especially for highly protein bound and water-soluble drugs.

Malnutrition

In protein-depleted states when the total serum drug concentration is within the therapeutic range, the unbound (free) fraction of highly protein bound drugs—for example, drugs binding to albumin—will be increased and may result in toxic effects. Thus, therapeutic levels of such a drug (reflecting the total serum concentration) will underestimate its potential for toxicity in malnourished patients. Free concentrations of highly protein bound medications with narrow therapeutic indices should be obtained in these patients. Severely malnourished patients may also have decreased hepatic drug metabolism.

Obesity

A relatively new challenge in health care is the management of patients who are overweight, obese, or morbidly obese (Chapter 29). Although this represents a growing proportion of patients, information regarding the pharmacokinetic changes in these patients is scarce. Information about the oral absorption of medications in obese patients is lacking, and it is unclear what changes occur in this population, if any. Patients undergoing gastric bypass represent an understudied population in regard to oral absorption of medications. No conclusion regarding altered absorption in this population can be made. Obese patients commonly have increases in cardiac output, total blood volume, and organ mass. These changes theoretically contribute to an increased volume of distribution; however, the clinical significance of this is unknown. Serum albumin and total protein are not altered in obese patients, thus distribution of medications that are significantly bound to plasma proteins should not change. Medications that are highly lipophilic may have higher volumes of distribution; however, not all lipophilic drugs distribute to adipose tissue. The decision of dosing a medication on a predicted or lean (also referred to as “ideal”), total, or adjusted body weight should be based on published clinical data. In general, the metabolism of drugs that undergo phase II conjugation may be increased, whereas the metabolism of drugs that undergo phase I metabolism can vary based on the specific cytochrome P450 enzyme involved.

Clearance of drugs dependent on glomerular filtration is significantly higher when compared to normal-weight subjects. Estimating the glomerular filtration of the obese patient is challenging, and common calculations for estimating CrCl may underestimate glomerular filtration.

The Elderly Adult Population

As the elderly adult population increases, it has become increasingly important to evaluate the use of medications within this population, including pharmacokinetic changes that may occur with normal aging. Although the technical definition for an elderly patient is a person 65 years or older, not all patients in this age category will exhibit the same pharmacokinetic changes. Variations in underlying health and comorbid states will affect pharmacokinetics to a greater extent than an absolute age. In general, elderly patients have elevated gastrointestinal pH, potentially impairing absorption of medications that are acid dependent. Elderly patients may also have delayed gastric emptying, which may decrease the rate but not the overall absorption of medications. Changes in body composition such as a decrease in lean muscle mass and a relative increase in adipose tissue commonly occur in these patients. Because of these changes, medications that are distributed to adipose tissue may have increased volumes of distribution and medications that are water-soluble may have decreased volumes of distribution. As patients age, the ability to metabolize drugs via hepatic oxidation is reduced, whereas the ability to metabolize those that undergo hepatic conjugation is comparatively well preserved. This decline in hepatic function may result in an increase in oral bioavailability of drugs with extensive first pass metabolism. A decrease in glomerular filtration commonly occurs as a patient ages and is closely correlated to increasing age. Medications that are eliminated by glomerular filtration will therefore require dosage reductions. Furthermore, certain medications that are unsafe to administer at reduced creatinine clearances may even be contraindicated in the elderly. There are numerous calculations for estimating CrCl in patients; however, no standard exists for the elderly. When using narrow therapeutic index medications, renal function should be carefully assessed, as many calculations will overestimate CrCl in the elderly population.

Mechanical Ventilation

Hemodynamic depression from mechanical ventilation may impair liver and renal function, especially in patients with high levels of applied positive end-expiratory pressure (PEEP) or auto-PEEP (>10 cm H₂O) and large tidal volumes (>10 mL/kg predicted body weight). Decreases in cardiac output may occur without hypotension.

Transdermal Drug Delivery

The drawbacks of the administration of medications via the transdermal route should be carefully considered in the critically ill population. Decreased perfusion to subcutaneous and epidermal tissue may make absorption erratic and unreliable for drug administration. Furthermore, certain medications such as fentanyl have increased absorption in febrile states, which may lead to adverse events from unpredictable drug administration. Certain other drugs (nicotine, clonidine, Androderm, or scopolamine) have patches with aluminum in their backing such that they may not be worn in a magnetic resonance imaging (MRI) machine or during cardioversion. Rapid escalation or de-escalation of dose is typically not possible because of the longer onset and offset of transdermal medications. Overall, caution should be used when choosing transdermal medications, and other more reliable routes of medication administration should be chosen when possible.

Aminoglycosides

Aminoglycoside antibiotics inhibit bacterial protein synthesis through irreversible binding to 30S ribosomal subunits. Amikacin, gentamicin, and tobramycin have activity against most gram-negative bacteria and are commonly administered parenterally for health care associated infections. Neomycin, the only orally available aminoglycoside, has poor bioavailability and is primarily used for hepatic encephalopathy or gut decontamination. When administered parenterally, aminoglycosides are rapidly distributed (30 minutes to 1 hour), mainly to extracellular body fluid, resulting in a small volume of distribution (0.15 to 0.35 L/kg). Aminoglycosides are excreted through glomerular filtration with elimination half-lives closely correlated to CrCl. In a patient with normal renal function, the elimination half-life is between 2 and 3 hours; however, this is dramatically increased in patients with renal insufficiency.

Aminoglycosides exhibit antibacterial activity through concentration-dependent killing, meaning that the ability to kill bacteria improves with increasing concentrations. The optimal pharmacodynamic parameter associated with aminoglycoside bactericidal activity is a peak-to-minimum inhibitory concentration (peak: MIC) ratio of 10:1. Several dosing strategies, including traditional (multiple daily dosing) and once-daily dosing, can be used to achieve this goal, although once-daily dosing has become more common. This dosing strategy maximizes peak concentrations, and thus bactericidal activity, while potentially minimizing toxicity by allowing for aminoglycoside free intervals. The result is a decrease in the risk for trough-related toxicities (nephrotoxicity).

Aminoglycosides, specifically gentamicin, are also used for synergistic effects against gram-positive organisms (Staphylococcus spp., Enterococcus spp., and Streptococcus spp.). The dosing strategy and goal peak concentrations for synergy differ from those associated with managing infections due to gram-negative bacteria. Table 17.1 contains dosing strategies and goal serum concentrations for traditional, once-daily, or extended interval and synergy dosing. Peak and trough concentrations are typically recommended for patients receiving traditional or synergy dosing. Peaks should be obtained at steady state, 1 hour after completing the infusion of the fourth or fifth dose. Troughs should be obtained at steady state prior to the fourth or fifth dose. A random level 6 to 14 hours after the first dose should be obtained in patients receiving once-daily or extended interval dosing. This level should be applied to various nomograms that aid in dosing. Figure 17.1 is the most commonly used nomogram, the Hartford nomogram. Patients on the borderline of a dosage interval should be dosed using the greater dosage interval. In patients receiving amikacin, the random level should be divided by 2 before applying the nomogram.