96 3.5 Excretion
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The fourth and final stage of ADME of pharmacokinetics is known as excretion. Excretion is the physical process by which drugs are removed from the body. In humans, excretion is primarily carried out by the kidneys (via urine), although other organs (e.g., lungs, skin, or gastrointestinal tract) may play a role for some drugs. Recall that elimination is the sum of the processes of removing an administered drug from the body, which includes both metabolism and excretion. Thus, excretion is part of the total elimination process of administered drugs.
For excretion of hydrophobic drugs, they typically require metabolic modification to make them more polar. Hydrophilic drugs, on the other hand, can undergo excretion directly, without the need for metabolic changes to their molecular structures.
3.5.1 Half-life
One of the most important concepts for the elimination of drugs is half-life. The half-life ([latex]t_{1/2}[/latex]) is the time required for the initial concentration of a drug to decrease by half within the blood plasma. It is typically represented by hours or days, and is determined by the volume of distribution (Vd) and clearance (CL), which is the volume of plasma cleared of a drug per unit time (i.e., mL/min). Half-life is typically represented by the following equation:
This measurement is useful in medicine to help determine the amount of drug that needs to be taken, how frequently it should be administered, and to prevent toxic effects. The half-life varies for each drug, ranging anywhere from minutes to upwards of days to months. For example, the drug norepinephrine, which is used to treat people with very low blood pressure, exhibits a half-life of 2 minutes. Conversely, fluoxetine, which is an SSRI used to treat depression, exhibits a half-life of 4 to 6 days. Half-life can be further complicated due to accumulation in tissues, formation of active metabolites, genetics, reaction kinetics, and drug interactions.
The value of half-life for any drug depends on the kinetics of the reaction. There are two major classifications of reaction kinetics, first-order and zero-order. Most drugs are eliminated by first-order kinetics.
First-order kinetics: the rate of the reaction depends on the concentration of the drug
Zero-order kinetics: the rate of the reaction does not depend on the concentration of the drug
Understanding reaction kinetics is clinically useful in achieving a therapeutic level of medication, assessing toxicity levels, and implementing treatment. While most drugs undergo elimination via first-order kinetics, a firm understanding of both zero and first-order kinetics is crucial in a clinical setting, as there can be fluidity between the two types of elimination with the same drug. To achieve the desired therapeutic level of a medication, a clinician must understand the elimination order and utilize the information in subsequent dosing to maintain the therapeutic concentration over a set period. Misunderstanding of kinetic elimination may lead to patients experiencing toxic symptoms and could lead to other adverse effects, including death.
The fundamental difference between zero and first-order kinetics is their elimination rate compared to the total plasma concentration (Fig. 3.18). Zero-order kinetics undergo constant elimination regardless of the plasma concentration, following a linear elimination phase as the system becomes saturated. The rate-limiting factor of zero-order kinetics is time. For example, ethanol is eliminated at a rate of approximately 15 mL/hour, regardless of the concentration in the bloodstream. This occurs because enzyme binding sites are often saturated at low drug concentrations. First-order kinetics proportionally increase elimination as the plasma concentration increases, following an exponential elimination phase as the system never achieves saturation. The initial concentration is the rate-limiting factor of first-order kinetics. Only a percentage (or fraction) of the initial dose is removed per unit of time, not a fixed amount (as in zero-order). This typically translates to the clearing of a drug between 4 to 5 half-lives. For example, cocaine has a half-life of approximately 1 hour; thus, less than 7% of the initial dose will be present within the body after only 4 hours.
Figure 3.18: Zero- and first-order elimination and equations. Obtained from: https://www.ncbi.nlm.nih.gov/sites/books/NBK499866/figure/article-31464.image.f1/?report=objectonly
In the case of methanol ingestion, urgent treatment is necessary. Methanol itself results in sedation but is generally nontoxic. The toxicity of methanol is a function of its metabolites. As methanol follows zero-order kinetic elimination, a clinician can understand that the actual danger lies in the time from the ingestion, not the total amount. In contrast to methanol, other specific medications that show zero-order elimination are salicylates, omeprazole, fluoxetine, phenytoin, and cisplatin, which, when ingested at toxic levels, achieve a higher concentration of the substance within the body over time, versus the same amount of the substance that uses first-order elimination.
3.5.2 Clearance
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In pharmacology, clearance (CL) is a pharmacokinetic parameter that measures the volume of plasma cleared of a drug per unit time (i.e., mL/min). Substances in the body can be cleared by various organs, including the kidneys, liver, lungs, etc. Thus, total body clearance (Cltot) is equal to the sum of the clearances by each organ (e.g., renal clearance + hepatic clearance + pulmonary clearance = total body clearance). For many drugs, however, clearance is solely a function of renal excretion. When referring to the function of the kidney, clearance is considered to be the amount of liquid filtered out of the blood that gets processed by the kidneys or the amount of blood cleaned per unit time. Each substance has a specific clearance that depends on how the substance is handled by the functional unit of the kidneys, the nephron. Clearance is a function of 1) glomerular filtration, 2) secretion from the peritubular capillaries to the nephron, and 3) reabsorption from the nephron back to the peritubular capillaries (Fig. 3.19). Excretion, on the other hand, is a measurement of the amount of a substance removed from the body per unit time (e.g., mg/min, μg/min, etc.). While clearance and excretion of a substance are related, they are not the same thing.
Figure 3.19: Diagram showing the basic physiologic mechanisms of the kidney. Obtained from: https://commons.wikimedia.org/wiki/File:Physiology_of_Nephron.png
Elimination kinetics play an essential role in drug clearance as well. In first-order kinetics, a constant fraction of the drug is cleared per unit time because the mechanisms used for elimination are not saturated. Thus, drug clearance does not vary with changes in the plasma concentration of a drug when drug elimination occurs by first-order kinetics. The vast majority of drug elimination takes place by first-order kinetics. In zero-order kinetics, the same quantity of drug is eliminated per unit time because the mechanisms used for elimination are saturated. In zero-order kinetics, drug clearance can vary due to changes in the plasma concentration of a drug.
3.5.3 Routes of Excretion
3.5.3.1 Renal
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The renal system consists of the kidney, ureters, and the urethra. The overall function of the system filters approximately 200 liters of fluid a day from renal blood flow, which allows for toxins, metabolic waste products, and excess ions to be excreted while keeping essential substances in the blood.
Renal excretion completes the process of elimination that begins in the liver. Polar drugs or their metabolites get filtered in the kidneys and typically do not undergo reabsorption. They subsequently get excreted in the urine. Urinary pH has a significant impact on excretion, as drug ionization changes depending on the alkaline or acidic environment. Increased excretion occurs with weakly acidic drugs in basic urine and weakly basic drugs in acidic urine.
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For example, alkalinization of the urine is an effective method to increase the clearance of salicylates (e.g., aspirin) from the body. Alkalinization of the urine causes salicylates to be trapped in renal tubules in their ionized form and then readily excreted in the urine. Alkalinization of the urine increases urinary salicylate excretion by eighteen fold.
Glomerular filtration will only remove those drugs or metabolites that are not bound to proteins present in blood plasma (free fraction) and many other types of drugs (such as the organic acids) are actively secreted. In the proximal and distal convoluted tubules, non-ionized acids and weak bases are reabsorbed both actively and passively. Weak acids are excreted when the tubular fluid becomes too alkaline and this reduces passive reabsorption. The opposite occurs with weak bases.
3.5.3.2 Biliary
As the liver filters blood, some drugs and their metabolites are actively transported by hepatocytes (liver cells) to the bile (stored in the gallbladder). The liver can actively secrete ionized drugs with a molecular weight greater than 300 g/mol into bile. The bile moves through the bile ducts to the gallbladder and then on to the small intestine. During this process, some drugs may be partially absorbed by the intestine back into the bloodstream. Unabsorbed drugs and byproducts/metabolites are excreted in the feces.
Enterohepatic circulation of drugs describes the process by which drugs are conjugated to glucuronic acid in the liver, excreted into bile, metabolized back into the free drug by intestinal bacteria, where the drug is then reabsorbed into plasma. For many drugs that undergo this process, lower doses of the drug can be therapeutically effective because elimination is reduced by the 'recycling' of the drug. For the majority of drugs that undergo enterohepatic circulation, inhibition of this process leads to a reduction of the levels of the drug and reduced therapeutic effect. For example, antibiotics that kill gut bacteria often reduce enterohepatic drug circulation, and thus require a temporary increase in the drug's dose until the antibiotic use is discontinued and the gut repopulates with bacteria. This effect of antibiotics on the enterohepatic circulation of other drugs is one of several types of drug interactions.
3.5.3.2 Other Routes to Consider
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Sweat, tears, reproductive fluids (such as seminal fluid), and breast milk can also contain drugs and byproducts/metabolites of drugs. This can pose a toxic threat, such as the exposure of an infant to breast milk containing drugs or byproducts of drugs ingested by the mother.
3.5.4 Factors Influencing Renal Excretion
3.5.4.1 Life Span Considerations
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Neonates and children have immature kidneys with decreased glomerular filtration, resorption, and tubular secretion. As a result, they do not excrete medications as efficiently from the body. Dosing for most medications used to treat infants and pediatric patients is commonly based on weight in kilograms, and a smaller dose is usually prescribed. In addition, pediatric patients may have higher levels of free circulating medication than anticipated and may become toxic quickly. Therefore, it is vital to diligently recheck dosages before administering medications and closely monitor infants and children for early identification of adverse effects and drug toxicity.
Kidney (and liver) function often decreases with age, which can lead to decreased metabolism and excretion of medications. Subsequently, medication may have a prolonged half-life with a greater potential for toxicity due to elevated circulating drug levels. Some medications may be avoided or smaller doses recommended for older patients due to these factors.
3.5.4.2 Kidney Disease
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Renal disorders, such as chronic kidney disease, can reduce renal function, hindering drug excretion. Chronic kidney diseases are not uncommon. Approximately 16.8% of the US population has chronic kidney disease (CKD). CKD is the presence of kidney damage with urinary albumin excretion of over 29 mg/day or decreased kidney function with glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 for three or more months. CKD involves a progressive loss of kidney function, often leading to the need for renal replacement therapy, such as dialysis or transplantation. Thus, management of CKD involves adjusting medication dosages according to the patient's GFR.
Other than direct renal dysfunction, pathologies that impact renal blood flow or urine flow can affect drug elimination as well. Examples of such disorders are congestive heart failure, liver disease, and pathologies affecting antidiuretic hormone release.
