and accumulation also demonstrates fundamental principles of diffusion: The attraction of molecules to move from areas of greater concentration toward regions of lower concentration in order to reach a state of equilibrium. Accumulation of a drug is of considerable importance for a movement-based clinical prac- titioner. Primary examples include bleeding risk for patients with anticoagulant accumulation in the body, as well as potentially le- thal effects of chronic opioid ingestion. Bioavailability is the frac- tion of unchanged drug in systemic circulation (Katzung, 2018, p. 47). This accounts for drug administration by any route, as well as first-pass metabolism for medications passing through the gastro- intestinal tract. As mentioned earlier, alternative methods of drug administration can bypass first-pass metabolism, thereby increas- ing bioavailability. Extraction rates are highly dependent upon first-pass effect and vary depending on pharmaceutical composi- tion and individual function of the liver, kidney and heart. Immediate effects of a drug can be directly correlated with the concentration present in blood plasma (Katzung, 2018, p. 48). Pharmaceuticals with large volumes of distribution maintain rela- tively high plasma concentrations in the presence of physiologic elimination, leading to accumulation. This phenomenon must be considered with regards to drug toxicity, prolonged drug action and cumulative physiologic effects in general. Delays in drug ef- fects are also subject to changes in plasma concentration. The most common effect delays represent the time from administra - tion to the time of drug molecules reaching sites of action. In ad- dition, drugs that create stronger bonds to receptors may require additional periods to disassociate before reaching systemic cir- culation and creating a steady state of equilibrium. Finally, effect delays may also be attributed to distribution and/or elimination of a given physiologic substance involved in pharmaceutical expres- sion (Katzung, 2018, p. 49). Current practice of pharmaceutical prescription is centered upon the concept of reaching a theoretical target concentration to ac- complish an optimal therapeutic effect. Following this ideal are concepts of maintenance and loading doses. A maintenance dose is a calculated dosage that maintains steady state target concen- tration of a drug and guides the process of 24-hour dosage rec- ommendations. Loading doses are additional administrations of a given drug that can decrease the time period required to reach a steady state. This concept is considerate of drugs with greater half-lives, as well as drugs that travel along multi-compartmental biological routes toward sites of action. Loading doses also pres- ent additional risk, as an increased rate of administration can lead to adverse effects, such as drug toxicity. A prescribing clinician uses a target concentration strategy to ac- count for variability regarding the amount of drug input into the body, clearance, and volume of distribution, to improve the dos- ing for an individual to achieve a desired physiologic effect. Input into systemic circulation is dependent upon the patient’s adher- ence to a given prescription, as well as the rate and magnitude of drug transferred from the site of administration into the blood (Katzung, 2018, p. 51). If overdosage or underdosage is suspect- ed, the primary site of concern is often the small bowel, where metabolism during absorption occurs. Age, comorbidities and pathologic conditions may affect the body’s ability to metabolize and eliminate pharmaceuticals. Liver, kidney, and/or heart dys- function may also impair drug clearance. Creatinine clearance is a common lab value to measure renal function. No such biological marker currently exists to detect changes in liver clearance, and hepatic pathologies may or may not affect drug clearance from the liver. On the other hand, measuring drug concentrations in the body over a period of time can provide valuable reference related to the organs’ abilities to eliminate a specific drug. 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 de- creases apparent volume. In turn, patients with decreased muscle mass, who are generally older in the absence of significant pathol-
agement and requires consideration of risks versus benefits. For a relatively benign problem, such as a headache, the therapeutic dose should be well below toxic potential. Conversely, an ag- gressive and potentially lethal pathology may warrant therapeutic dosages that present a degree of toxic side effects. As well, an individual’s response to a given dosage may be vari- able. Drug response variation depends upon clinical observation of the individual. Some people even demonstrate idiosyncratic responses, meaning that a given dose may produce erratic re- sponses from one dosage to the next. Patient responses can also be assessed as hyperreactive versus hyporeactive, depending on the normative effects over a large population. Tolerance for a giv- en pharmaceutical may also present over a long course of phar- macotherapy, most often in the form of decreased physiologic response to a consistent dosage. Mediating therapeutic versus toxic effects is performed by three primary methods (Katzung, 2018, p. 39): 1. A pharmaceutical should always be prescribed at the lowest dose that will produce adequate benefit. 2. Complimentary drugs that produce similar physiologic effects via different receptor mechanisms may afford decreasing dosages of a given primary drug to reduce toxic effects. Example: Prescription of additional immunosuppressant agents in the presence of glucocorticoids to reduce inflammatory response. 3. Drug concentration may be directed by administration to specific parts of the body. Example: Aerosol administration of glucocorticoids directly to pulmonary bronchi for asthma treatment. Pharmacokinetics Actions of the body upon a drug are termed pharmacokinetics , and accounts for physiologic variables such as body size, age, gender, comorbidities, etc. Primary pharmacokinetic constraints include volume of distribution and clearance. Volume of distri- bution indicates the perceptible physical space available within the body to contain a given drug and is typically quantified by liters/mass concentration; i.e. liters/kilogram (Katzung, 2018, p. 42). Volume of distribution is dependent upon individual body as well as drug compositions, and may be computed with respect to blood, plasma and/or water. In turn, volume of distribution may exceed physical volume in the body, as certain unbound drug molecules may occupy extracellular space (i.e. outside the cell). In contrast, drugs that are completely encompassed within the vas- cular system will have relatively limited access in terms of volume of distribution. With respect to single adult doses, chloroquine, a compound used to treat and prevent malaria, presents a volume of distribution of 13,000 L/70 kg, while aspirin occupies merely 11 L/kg. Clearance refers to the rate the drug is expelled from the body and is expressed as a volume of plasma from which the drug is re- moved per unit time, e.g. milliliters/minute. Clearance rate mea- surement can be taken in terms of specific elimination pathways, such as urine and/or biliary secretion, as well as total systemic clearance. Drug clearance rate can be affected by physiologic function and associated changes in volume of distribution. A com- mon example is chronic renal failure. Impaired kidney function can reduce clearance rates for many pharmaceuticals. As well, chronicity of the disease is often associated with muscle wasting, leading to decreased skeletal mass, and thus reduced volume of distribution. A drug’s elimination “half-life” refers to the time it takes to re- duce its steady state concentration in plasma by 50 percent. This measure is widely employed to estimate required time between pharmaceutical dosing. Half-life is an exponential value. The rule of thumb is that a drug is completely eliminated from the body in approximately four half-lives. This guidepost also factors into measurement of drug concentrations during constant infusion. Accumulation of a pharmaceutical in the body can also be quanti- fied as an inverse to the proportion of a drug lost over the course of a given dosing interval. The relationship between elimination
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