97 3.6 How Pharmacokinetics Impacts Medicine
3.6.1 Determining Dosage
In medicine, the treatment for most conditions uses various pharmacological medications. For each of these individual medications, the route of administration, appropriate dosage, and frequency of use are determined by the medication’s pharmacokinetics (PK). As we have discussed in this chapter, pharmacokinetics is the relationship between an administered dose of a drug and its measured concentration within the body. An individual medication’s PK is governed by how it moves within the body through absorption, bioavailability, distribution, metabolism, and excretion.
The characteristics that define an individual medication’s PK can help determine the correct dose. While a patient takes a specific drug to achieve the therapeutic benefit, the drug must reach a certain steady-state concentration. Steady-state is a concept of fundamental importance in pharmacology. It describes a dynamic equilibrium in which drug concentrations consistently stay within therapeutic limits for long, potentially indefinite, periods. The concentration around which the drug concentration consistently stays is known as the steady-state concentration. Following repeated administration of a drug, a steady-state is reached when the quantity of drug eliminated in the unit of time equals the quantity of the drug that reaches the systemic circulation in the unit of time. This typically occurs within four to five half-lives of the drug.
When the bioavailability of a drug, the Vd, and the body’s CL of a drug are known, we can calculate the dosage of a medication. A loading dose (LD) is a relatively large dose of the drug can be administered to reach a therapeutic or steady-state concentration more rapidly. A maintenance dose (MD) is the periodic administration of the drug to maintain therapeutic concentrations. These types of dosing can be calculated using the following formulas:
Formula Legend: LD = loading dose; MD = maintenance dose; SSC = desired steady-state concentration of the drug; Vd = volume of distribution; B = drug bioavailability; CL = clearance; DI = dosing interval
Reaction kinetics must also be considered for dosing. If the absorption and elimination systems are not saturable for small dosing increments, the increase in the concentration of the drug is proportionate. In this case, the drugs follow first-order kinetics. On the other hand, if the absorption and elimination systems are saturable, a zero-order (or saturation) kinetics is followed. In this model, the kinetics is not exponential but initially linear as drug removal occurs at a constant speed, originally independent from the plasma concentration. After saturation, the relationship between the administered dose and the steady-state plasma concentration is unpredictable, not following the rule of proportionality. When the system is saturated, indeed, increases in the administered dose will not correspond to increases in plasma concentrations, and small changes in dose may induce a significant change in plasma concentrations. Several drugs such as ethanol, phenytoin, and aspirin exhibit the saturation kinetics, especially at toxic concentrations.
3.6.2 Defining the Therapeutic Window
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For every drug, there exists a dose that is minimally effective and another dose that is toxic. Between these doses is the therapeutic window, where the safest and most effective treatment will occur. For example, let’s examine the therapeutic window for warfarin, a medication used to prevent blood clotting (Fig. 3.20). Too much warfarin administered causes bleeding and vitamin K is required as an antidote. Conversely, not enough warfarin administered for a patient’s condition can cause clotting. Think of the therapeutic window (the green area on the graph) as the “perfect dose,” where clotting is prevented and yet bleeding does not occur. The effect of warfarin is monitored using a blood test called international normalized ration (INR). For patients receiving warfarin, we must monitor their INR levels to ensure the dosage appropriately reaches their therapeutic window and does not place them at risk for bleeding or clotting.
Figure 3.20: The therapeutic window of warfarin. Obtained from: https://www.ncbi.nlm.nih.gov/books/NBK595006/figure/ch1pharma.F1.9/?report=objectonly
3.6.3 Adjusting for Patient Variation
There are many patient variables that must be accounted for when a patient is prescribed medication, including changes in absorption, distribution, metabolism, and excretion (ADME) due to aging.
Aging does not significantly affect the extent of drug absorption, but the absorption rate may be slower. As a result, the peak serum concentration of a drug may be lower, and the time to reach it may be delayed in older patients. However, the overall amount absorbed (bioavailability) does not differ in patients based on age. Exceptions include drugs with an extensive first-pass effect that may have higher serum concentrations or increased bioavailability as liver size and hepatic blood flow decrease with aging because the liver extracts less drug. Other factors impacting drug absorption include how medications are taken, what it is taken with, comorbidities, or inhibition or induction of enzymes in the gastrointestinal (GI) tract.
Recall that distribution is the extent to which a drug penetrates the body and the rate at which it spreads throughout the body, which is represented by volume of distribution (Vd). Older adults have less body water and lean body mass; therefore, hydrophilic (water-soluble) drugs have a lower volume of distribution. Another specific change with aging is increased fat stores. In some elderly individuals, body fat increases (up to 36% in men and 45% in women) result in an increased volume of distribution for lipophilic (fat-soluble) drugs. Albumin, the primary plasma protein to which drugs bind, is usually lower in older adults. Because of that, there is a higher proportion of unbound (free) and pharmacologically active drugs, which is not a problem in younger patients, as additional unbound drugs are typically eliminated. However, there is a decrease in elimination with aging, resulting in the accumulation of unbound drugs in the body.
Recall that metabolic conversion of drugs occurs via phase I/II reactions in the liver, intestinal wall, lungs, skin, kidneys, and other organs. With aging, there is a decrease in hepatic blood flow and liver size, and the clearance of some drugs by the liver may be decreased by up to 30% in older adults. The phase I reactions, catalyzed by cytochrome P450, are more likely to be impaired in older people than phase II reactions; thus, medications metabolized through phase II pathways are preferred for older adults.
Excretion refers to a drug's final exit routes from the body. The liver and kidneys eliminate many known drugs. Hepatic or renal dysfunction can alter the pharmacokinetics of drug elimination, changing a drug’s half-life. With aging, renal size and blood flow decrease, and glomerular filtration declines. Consequently, the time to steady-state concentration can change. Although the drug’s loading dose generally does not need to be changed, if the same steady-state concentration is desired, the drug’s maintenance dose (drug addition) should be adjusted to compensate for the change in elimination (drug removal).
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The effects of many drugs are altered in renal impairment, particularly when a drug is renally cleared. Drug doses should be altered based on the predicted reduction in the clearance of the drug. Patient factors, such as the degree of renal disease and patient size, also influence the decision to adjust drug doses. In addition, drug factors, including the drug excretion and the therapeutic index, must be considered when adjusting doses. Accurate estimation of renal function is crucial for determining appropriate doses of renally excreted drugs. In patients with renal impairment, the dosing of renally cleared drugs has to be adjusted based on the patient's actual GFR.
Renal disease can alter drug concentrations and effects in the body, occasionally reducing effects but more commonly escalating their effects and thus causing potential toxicity. Most of these changes are predictable and may be prevented by altering drug doses in accordance with established guidelines.
Renal disease primarily affects drug dosing in three ways:
Patient susceptibility: Patients with renal impairment may be more vulnerable to a specific drug effect.
Pharmacodynamic change: The effect of a drug may be increased or decreased in patients with renal disease.
Pharmacokinetic changes: When given at usual doses, some drugs have higher steady-state concentrations in patients with renal impairment.
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Alcohol metabolism has been extensively studied through pharmacogenetics. The primary enzymes involved in alcohol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Their encoding genes exhibit polymorphisms that impact metabolism. Specific gene variants of ADH are associated with faster or slower metabolism, where slow metabolizers exhibit a higher probability of alcohol-related toxicities. Polymorphisms also occur in ALDH. The ALDH polymorphic phenotypes include rapid metabolizers and slow metabolizers. Expression of an inactive form of the ALDH2 isoenzyme, commonly found in East Asian populations, results in impaired acetaldehyde metabolism (leading to acetaldehyde accumulation), with apparent symptoms including flushing, nausea, and vomiting. Differences in ADH and ALDH may contribute to the genetically determined predisposition for excessive alcohol intake.
Variations in CYP genes can lead to significant interindividual differences in drug metabolism, with prevalence varying across different populations and ethnic groups. For instance, CYP2C19 polymorphisms play a crucial role in the metabolism of proton pump inhibitors (PPIs) and certain antiplatelet medications. A study demonstrated that co-administration of omeprazole with clopidogrel resulted in a 30% reduction in platelet aggregation inhibition compared to clopidogrel alone. Identifying these genetic differences allows for more personalized treatment approaches, reducing adverse drug reactions and improving therapeutic outcomes. Variations in CYP2D6 can impact the metabolism of opioids, antidepressants, and antipsychotics. Atomoxetine, a selective serotonin/norepinephrine reuptake inhibitor, undergoes hepatic metabolism that is subject to CYP2D6 polymorphism. The physiologically based pharmacokinetic features of atomoxetine differ among various CYP2D6 genotypes. Therefore, the starting dose needs to be reduced in poor metabolizers to prevent elevated serum drug levels. By integrating CYP testing into clinical decision-making, healthcare providers can tailor drug therapy more precisely, enhancing both efficacy and safety in patient care.
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Drug transporters are involved in drug absorption, distribution, and elimination, as they determine a drug's fate in the body. These transporters are proteins that regulate the transportation of drugs by facilitating or restricting their movement across cellular membranes. The genes and variants of these transporters, subject to the nature of polymorphism, may exhibit different transport behaviors and result in varied outcomes. Drug-transporting systems are classified into 2 major families as follows:
ATP-binding cassette (ABC) transporters are active efflux mechanisms that utilize ATP to extrude drugs against concentration gradients.
Solute carrier (SLC) transporters facilitate passive or secondary active transport of drugs across cellular membranes.
ABC transporters are transmembrane proteins that transport both exogenous and endogenous compounds, including sterols, lipids, and drugs. Among these transporters, ABCB1, also known as P-glycorprotein (P-gp), is a key efflux pump that has been extensively studied for its role in drug transport and multidrug resistance. ABCB1, also known as P-gp and multidrug resistance protein-1, is an ATP-dependent efflux transporter found in various tissues, including the intestines, liver, kidneys, blood-brain barrier, and placenta. ABCB1 plays a crucial role in drug absorption, distribution, and elimination by actively pumping drugs out of cells. Some variants of this transporter have been associated with altered drug efflux and variable responses to antiepileptics, chemotherapeutics, and cardiovascular drugs.
Organic anion transporting polypeptides (OATPs), a type of solute carrier, transport large, hydrophobic anions and mediate hepatic drug uptake. Polymorphisms in these transporters influence drug pharmacokinetics, underscoring their significance in pharmacological therapy. OATP1B1, encoded by SLCO1B1, is specifically expressed on the basolateral membrane of hepatocytes (liver cells) and plays an indispensable role in the hepatic uptake and elimination of negatively charged organic compounds. Substrates of OATP1B1 include bile salts, steroid hormones, statins, bilirubin, thyroid hormones, prostaglandins, methotrexate, irinotecan, repaglinide, and some antiviral and anticancer drugs. Statins are known to be subject to SLCO1B1 polymorphism. Drug interactions with statins occur every day during combination therapy, according to numerous published studies. For instance, when statins are used in combination with cyclosporine, rifampin, and gemfibrozil, excessive exposure to statins may occur, potentially leading to rhabdomyolysis and life-threatening consequences due to drug interactions inhibiting the function of OATP1B1.
3.6.4 Polypharmacy
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Polypharmacy, defined as the regular use of five or more medications at the same time, is common in older adults and at-risk younger individuals. As aging individuals often contend with multiple chronic health conditions, the use of five or more medications becomes common, posing risks of adverse outcomes such as falls, frailty, disability, and mortality. As the United States grapples with one of the highest medication rates worldwide, healthcare providers face the challenge of optimizing medication use to enhance patient outcomes.
Even though persons 65 years and older comprise about 14% of the total population, they account for over 33% of outpatient spending on prescription medications in the United States. Based on a recent population bulletin, the number of people aged 65 and older is projected to more than double from 46 million today to more than 98 million by 2060. Aging places individuals at risk of multi-morbidity (coexistence of two or more chronic health conditions) due to associated physiological and pathological changes and increases the chances of being prescribed multiple medications. This can lead to adverse drug effects, drug interactions, and prescribing cascades (i.e., multiple drugs). Polypharmacy increases the possibility of prescribing cascades when additional drugs are prescribed to treat the adverse effects of other drugs by misinterpreting the effect as a new medical condition. Polypharmacy can be overlooked because of the symptoms it causes as a result of drug interactions or side effects of drugs, for example, tiredness, sleepiness, decreased alertness, constipation, diarrhea, incontinence, loss of appetite, confusion, falls, depression, or lack of interest in usual activities, may be confused with symptoms of normal aging or sometimes lead to the prescription of more drugs to treat the new symptoms.
An adverse drug effect (ADE) is an injury from drug use. An adverse drug reaction (ADR) is an ADE that refers to harm caused by a drug at usual dosages. ADEs are estimated to be 5% to 28% of acute geriatric medical admissions. Preventable ADEs are among the severe consequences of inappropriate medication use in older adults. The drug classes commonly associated with avoidable ADEs are cardiovascular drugs, anticoagulants, hypoglycemics, diuretics, and NSAIDs. Adverse drug effects are higher in older adults due to metabolic changes and decreased drug clearance that come with age. This risk compounds when increasing the number of drugs used.
Multiple medications increase the potential for drug-drug interactions and the prescription of potentially inappropriate medications. A drug-drug interaction refers to the pharmacologic or clinical response when a drug combination is administered that differs from the response expected from the known effects of each agent when given alone. Cardiovascular drugs are most commonly involved in drug-drug interactions. The most common adverse drug interactions-related adverse events are neuropsychological (delirium), acute renal failure, and hypotension.
Polypharmacy increases the possibility of prescribing cascades when additional drugs are prescribed to treat adverse effects of other drugs by misinterpreting the ADE as a new medical condition; clinical examples are reported in the literature. Polypharmacy can be overlooked because of the symptoms it causes as a result of drug interactions or side effects of drugs, for example, tiredness, sleepiness, decreased alertness, constipation, diarrhea, incontinence, loss of appetite, confusion, falls, depression, or lack of interest in usual activities, may be confused with symptoms of normal aging or sometimes lead to the prescription of more drugs to treat the new symptoms.
