Volume of distribution is reflective of the amount of drug bound versus unbound within the body. Higher concentrations of drug bound to target tissues increases the apparent volume, while increased concentrations of drug bound to plasma proteins decreases apparent volume. In turn, patients with decreased muscle mass, who are generally older in the absence of significant pathology, tend to present with lower volumes of distribution for many pharmaceuticals that bind to muscle proteins (Katzung, 2018, p.52). On the other hand, pharmaceutical distribution for patients presenting with obesity depends largely on chemical drug properties, specifically whether or not the drug is hydrophobic versus hydrophilic. Volume of distribution may appear greater for hydrophilic drugs administered to patients with obesity. The opposite may be true for hydrophobic drugs, which enter fatty tissues more easily. Even though volume of distribution in this scenario may present as relatively low, the concern is that prolonged storage of pharmaceuticals in adipose tissue can lead to toxicity. In addition, volume of distribution may significantly increase for patients with pathologic fluid collection, such as ascites, pleural effusion, and/or edema, when hydrophilic drugs are administered. Maximum effect refers to the point at which increasing drug concentration does not produce changes in drug action. Determining maximum effect provides a quantitative marker with which to avoid overdosage and resultant toxicity. Sensitivity is the concentration of drug required to produce 50 percent of the maximum effect. The relationship between sensitivity and drug concentration also provides clinical data in the presence of pathological states. Increased drug sensitivity is associated with small amounts of a drug producing embellished responses. On the other hand, decreased drug sensitivity would be associated
with larger amounts of a drug producing relatively weak responses. Sensitivity values may be indicative of physiologic impairment and/or pharmaceutical antagonism. Clinical treatment often requires taking blood samples for the purpose of recording physiologic markers related to protein- binding. The following markers provide interpretive data related to drug dosage, organ blood flow, and fundamental function of the liver and kidneys (Katzung, 2018, p. 53). The primary proteins utilized for this purpose are albumin and alpha-acid glycoprotein. Pathologic conditions can decrease concentrations of serum albumin, thereby reducing total drug concentration. Conversely, acute and/or chronic inflammatory responses can increase alpha-acid glycoprotein concentrations, which can induce changes in total plasma concentration of certain drugs. In addition, drug concentration may be dependent on the capacity of a specific binding protein. Higher drug concentrations can lead to saturation when no unbound proteins are available and/ or present, which leads to an increased presence of unbound drug in plasma. Some pharmaceuticals demonstrate a higher affinity to red blood cells. In turn, fluctuations in red blood cell concentrations, correlated with hematocrit levels, may lead to changes in whole blood concentrations of a drug without changes in pharmacological activity. Measurement peak pharmacological concentration is relatively weak in terms of validity, and complicated by pharmacodynamics as well as pharmacokinetic variability. Greater effort is placed upon timing lab values to establish achievement of steady- state concentration. Although initial predictions for volume of distribution and clearance can be calculated, clinically significant differences in observed drug concentrations require dosing revisions.
PHYSIOLOGIC VARIABILITY
It is important to recognize and understand that every medication presents risks of side effects. In turn, side effects must be prevented, minimized and managed by allied health professionals (Watkins, 2013, p. 18). Mild pharmaceutical side effects include nausea, drowsiness, dizziness, constipation and sensitivity to light. An adverse reaction is a critical side effect, which may include shock and/or death, and often causes prescribers to amend medication prescriptions. Side effects may be unique to an individual patient and are termed idiosyncratic . In general, topical drugs present fewer side effects than systemic drugs. Side effects can also be described further by categorizing effects on specific organ systems. Neurologic drug effects can include hallucinations, agitation, depression, sedation, disorientation and even coma. As the primary cite of metabolism, side effects on the liver are generalized to organ damage due to local accumulation of a drug. Most common side effects are observed in the gastrointestinal system and include diarrhea, constipation, inflammation, nausea and vomiting. Gastrointestinal side effects can be mediated by food ingestion and dietary amendments. One of the most notable gastrointestinal side effects may include ulceration associated with long-term application of nonsteroidal anti-inflammatory drugs. Kidney damage may be implicated for specific medications that are metabolized primarily in the kidney as opposed to the liver. Impaired kidney function can lead to toxic pharmaceutical build-up in the body. Other medications are associated with ototoxicity, leading to hearing and/or balance loss. The hematological system is of notable concern as well. Certain drugs can lead to problems with coagulation, bleeding, clotting and/or immunosuppression (Watkins, 2013, p. 19). Damage to bone marrow is of specific concern with regard to anticancer drugs, as blood cell production is required for effective immune system response. Additional considerations for medication administration include age, gender and cultural background. Geriatric patients, defined as those 55 and older, present with decreased functional capacity for absorption and distribution. This can
be attributed to decreased gastrointestinal performance, abdominal blood vessel blockage, decreased plasma protein levels with consideration to nutritional status, and reduced liver and kidney function (Watkins, 2013, p. 31). Specific drug categories that present additional risk to elderly patients include sedative-hypnotics, such as non-steroidal anti-inflammatory drugs and anticoagulants, antihypertensive pharmaceuticals and thrombolytics (These categories will be further defined later in the course). Geriatric patients often require regimens of multiple medications, which increase the risk of adverse polypharmacy reactions due to drug interactions and side effects. On the other end of the age spectrum, pediatric patients present with increased metabolism, decreased body weight, reduced blood-brain barrier, and immature renal, endocrine and nervous system function. In turn, drug metabolism and excretion are relatively limited. Medication dosing can be complicated and dynamic due to rapid physiologic development, requiring an extraordinarily specific prescription to avoid potentially adverse effects. Considerations for injections include reduced arm muscle size, fragile blood vessels and general fear of needles. This presents needs for thigh muscle injection sites, careful monitoring during intravenous fluid administration, and gentle explanation and sensitivity in terms of approach (Watkins, 2013, p. 32). Absorption rates for neonates are reduced due to higher gastric pH, and more variable due to irregular stomach emptying times. As well infants secrete less lipase, which reduces absorption for lipid-formulated medications. Infants also have thinner striatum corneae, which increases absorption rates for ophthalmic pharmaceuticals. Pharmaceuticals that are introduced rectally are absorbed faster in pediatric patients, which can lead to rapid toxicity. The percentage of extracellular, total water and ratio of water to lipids is also higher for this population. In turn, drugs become more widely distributed throughout the body, though with reduced relative levels in the bloodstream (Watkins, 2013, p 32).
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