Chapter 15 Marini Pharmacotherapy

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CHAPTER 15 • Pharmacotherapy

absorption, whereas any factor that delays gastric emptying is expected to have the opposite effect, regardless of the characteristics of the drug. Enteral feeding may also affect drug absorption. Drugs given through an enteral feeding tube may adhere to the lumen of the tube (e.g., phenytoin, warfarin, amiodarone) or have incompatibilities with feeding tube formulations that limit bioavail- ability (e.g., fluoroquinolone antibiotics bind to cat- ions in the tube feeds). Given the physiologic shunting of blood to vital organs during shock, drugs may be slowly absorbed if given via the subcutaneous route. Common drugs used this way include insulin, UFH, and LMWH. Rates of absorption vary widely depending on the specific drug and local blood flow. In patients who are on vasopressor therapy or have more than a 10-kg fluid weight gain, the subcutaneous route should be considered less than normally reliable. Distribution and Protein Binding The distribution of a drug depends largely on two things: hydrophilicity and acid dissociation con- stant. During critical illness, changes in protein concentrations are known to occur that affect both the free (active) amount of drug available and the overall volume of distribution ( V d ). Generally, decreased protein binding leads to increased free drug and overall increased V d . Albumin concen- trations are usually decreased during critical ill- ness secondary to increased vascular permeability and decreased production and catabolism, thereby increasing the potential amount of free drug avail- able. Hypoalbuminemia generally affects drugs that carry an acidic or neutral charge (e.g., amiodarone, midazolam, morphine, phenytoin, propofol) because these bind well to albumin. Conversely, alpha-1 gly- coprotein concentrations increase during times of stress. This leads to lessened activity of drugs hav- ing basic charge (e.g., azithromycin, carvedilol, fen- tanyl, nicardipine, phenobarbital) because they are bound to alpha-1glycoprotein. Hydrophilic drugs (high-water solubility) have lower volumes of distribution than lipophilic (high- lipid solubility) drugs. Hydrophilic drugs (e.g., beta- lactams, vancomycin, aminoglycosides, morphine, hydromorphone) tend to distribute within the plasma volume and consequently depend on tissue perfusion for distribution. Therefore, in patients with poor perfusion secondary to shock (especially

those on vasopressors) or disease state (peripheral vascular disease, diabetes), hydrophilic drugs will not distribute as well. In contrast, lipophilic drugs (e.g., azithromycin, fluoroquinolones, fentanyl, midazolam, propofol) have sufficient volumes of distribution to penetrate tissues, independent of perfusion. Therefore, lipophilic drugs are minimally affected by shifts in fluid (as may be seen in large- volume fluid resuscitation). Generally speaking, lipophilic drugs are minimally affected by changes encountered in critical illness. Metabolism The liver has a major role in the metabolism of many drugs, and critical illness, along with drug proper- ties (extraction ratio and protein binding), can affect hepatic clearance. Hepatic drug elimination depends on blood flow, intrinsic clearance (the sum of all hepatic enzyme and transport activity involved in the removal of drug from the blood), and drug protein binding. Hepatic blood flow is likely to be impaired dur- ing hypovolemia or cardiogenic/hemorrhagic shock. Mechanical ventilation may impede venous return and hepatic blood flow. Drugs with high extrac- tion ratios (e.g., fentanyl, morphine, nitroglycerin, propofol) depend more on blood flow to the liver than on protein binding or enzyme function and will be most affected in these conditions. Conversely, metabolism of drugs with low extraction ratios (e.g., ceftriaxone, fluconazole, lorazepam, methadone and many others) depend less on hepatic blood flow and more on protein binding and enzyme function; these are significantly affected by moderate or severe liver failure or cirrhosis. Elimination Although the kidneys eliminate most drugs and their metabolites (through glomerular filtration and tubular secretion), drug elimination can also take place via the biliary tract, feces, and respira- tion. Dosing adjustments for drugs at steady state is calculated by estimating creatinine clearance (often using the Cockgroft–Gault or Jelliffe equations). When severe oliguria or anuria develops, however, it is difficult to assess true renal function. Critical illness can lead to augmented renal clearance, especially in patients who are less than 55 years of age, after trauma, (particularly head