Pharmacy Foundations Part 2 PDF

PHARMACY FOUNDATIONS PART 2 CHAPTER CONTENT With Background •• • • •• • ••• • • ••• •••• • 1009 Absorption •••• ••••• •• •• •• • •• ••• •• •• • •• • ••••• ••• •• •• •••1009 1010 Drug Absorption 1010 Local vs Systemic Effects 1010 Dosage Form Dissolution and Drug Solubility 1010 Bioavailability 10...

PHARMACY FOUNDATIONS PART 2 CHAPTER CONTENT With Background •• • • •• • ••• • • ••• •••• • 1009 Absorption •••• ••••• •• •• •• • •• ••• •• •• • •• • ••••• ••• •• •• •••1009 1010 Drug Absorption 1010 Local vs Systemic Effects 1010 Dosage Form Dissolution and Drug Solubility 1010 Bioavailability 1011 Bioavailability Formula 1011 Distribution 1012 Calcium and Phenytoin Correction Formulas 1012 Volume of Distribution . 1012 m Volume of Distribution ( Vd) Formula • a . r% * c o Loading Dose i i * X3 g i \ * * \ s 3 c <D U Steady State c o u No Loading Dose (Maintenance Dose Only) Time 1013 Metabolism Excretion .... '£) I * . Clearance and Area Under the Curve .... . Zero vs First Order Pharmacokinetics Michaelis-Menten Kinetics Dose Adjustments for Michaelis - Menten Kinetics t* Elimination Rate Constant £ Predicting Drug Concentrations tl Half- Life (t ,) and Steady State. ( Loading Dose Loading Dose ( LD) Formula Therapeutic Drug Monitoring 1013 1013 1015 1015 1015 1016 1016 1017 1019 1019 1019 CHAPTER 78 PHARMACOKINETICS BACKGROUND Pharmacokinetics is what the human body does to a drug and pharmacodynamics is what the drug does to the human body. Pharmacokinetics involves the study of drug absorption , distribution , metabolism and excretion (often abbreviated ADME ) over time. Mathematical relationships are used to describe these processes. Clinicians use pharmacokinetics to assess drug levels and optimize drug therapy. Pharmacodynamics refers to the relationship between the drug concentration at the site of action , and both therapeutic and adverse effects. ABSORPTION When a drug is given intravascularly (e.g., intravenously or intra arterially ) , absorption is not required because the drug directly enters the bloodstream (systemic circulation ) . If a drug is administered extravascularly, drug absorption occurs as the drug moves from the site of administration to the bloodstream ( see Study Tip Gal on the next page ). Some examples of extravascular administration include oral, sublingual, buccal, intramuscular, subcutaneous, transdermal, inhaled , topical , ocular, intraocular, intrathecal and rectal. When a drug is given orally, it passes from the stomach to the intestine. Most oral drug absorption occurs in the small intestine because of the large surface area and permeable membrane. After gut absorption , the drug enters the portal vein and travels to the liver. Some drugs are extensively metabolized in the liver before reaching the systemic circulation; this is called first pass metabolism (discussed later) . Some drugs are transported through the bile back to the gut where they can be reabsorbed. This is called enterohepatic recycling (see the Learning Drug Interactions chapter ) . CONTENT LEGEND t I = Study Tip Cal n I* Required Formula Absorption of oral drugs occurs via two primary processes: passive diffusion across the gut wall or active transport. Passive diffusion is movement of drugs from an area of high concentration (e.g., the gut lumen) to an area of lower concentration (e.g., the blood ) . Energy is not required for passive diffusion. Active transport occurs when drugs are moved across the gut wall via transporter proteins that are normally used to absorb nutrients from food. 11 78 | PHARMAC 0KINETIC 5 DRUG ABSORPTION N ‘ ' • •; % Oral . Sfomoch Smoll intestine Hepatic portal vein Enterohepatic Recycling Systemic Circulation LOCAL VS SYSTEMIC EFFECTS Drugs administered extravascularly can be divided into two categories: drugs intended for local effects and drugs intended for systemic effects. Drugs intended for local effects are often applied topically where the drug effect is needed. Examples of this include eye drops for glaucoma (e.g., latanoprost ) , dermal preparations for psoriasis (e.g., coal tar preparations) and nasal sprays for allergies (e.g., fluticasone nasal spray). Topical administration of a drug can produce therapeutic effects while minimizing systemic toxicity due to lower systemic exposure, but some topical formulations are designed to deliver a systemic dose (e.g., Duragesic patch). The extent of topical absorption is affected by many factors, including presence of open wounds on the skin ( increased absorption ) and the amount of drug applied. Drugs intended for systemic effects are generally administered to facilitate absorption to the circulatory system. Examples of drugs intended for systemic effects are oral tablets for seasonal allergies (e.g., loratadine) , suppositories for fever (e.g., acetaminophen ) and sublingual tablets for angina (e.g., nitroglycerin SL). Some percentage of a drug intended for systemic effect moves from the site of administration into the systemic circulation . DOSAGE FORM DISSOLUTION AND DRUG SOLUBILITY When an oral dosage form is ingested, it begins to dissolve in the gastrointestinal (GI ) tract and the active ingredient is released from the dosage form ( typically a compressed tablet or a capsule) . This is called dissolution. The rate of dissolution depends on the inactive ingredients used to make the dosage form . Drugs that dissolve rapidly in the mouth [e.g., sublingual (SL ) and orally dissolving tablet (OPT) formulations] will have faster absorption. Many drugs are made using polymers that help slow down the release of the drug in a controlled way. This can provide less variability in drug concentrations and reduce the dosing frequency. In general, the rate of absorption by dosage form will follow this order (fastest to slowest ) : IV, SL, ODT, immediate release tablet, extended release tablet. Most immediate release formulations dissolve and get absorbed rapidly, but some can be destroyed in the gut ( primarily by hydrolysis, or lysis with water) making them less available for absorption. Drug formulations have been developed with protective coatings to limit drug degradation in the stomach (acidic) but permit dissolution in the intestine ( basic). Examples of drugs with these protective coatings include enteric coated formulations such as Dulcolax and Entocort EC . If a drug has poor absorption , one of the methods used to increase the dissolution rate is to reduce particle diameter, which increases surface area. Drugs with very small particle diameters are referred to as micronized , which means the diameter was measured in micrometers, but sometimes refers to even smaller particle sizes measured in nanometers, Progesterone and fenofibrate are examples of drugs with poor oral absorption that have been developed in micronized formulations. The rate of dissolution is described by the Noyes-Whitney equation. Following dissolution , the drug that is released from the dosage form can be dissolved in GI fluids. The rate and extent to which the drug dissolves depends on the drug's solubility. Poorly soluble drugs are generally lipophilic, or lipid -loving. Freely soluble drugs are generally hydrophilic, or waterloving. As a drug moves through the GI tract, only dissolved drug is absorbed into the bloodstream. Poorly soluble drugs generally have poor systemic absorption, and highly soluble drugs often have good systemic absorption. BIOAVAILABILITY The extent to which a drug is absorbed into the systemic circulation is called bioavailability. Bioavailability is the percentage of drug absorbed from extravascular (e.g., oral ) relative to intravascular administration (e.g., IV ) . It is affected by absorption, dissolution, route of administration and other factors. Bioavailability is reported as a percentage from 0 to 100%. A drug with good absorption has high bioavailability (> 70%) , while a drug with poor absorption has low bioavailability (< 10%) . Levofloxacin and linezolid have high bioavailability. With these two drugs, nearly 100% f the oral dose is absorbed, and the oral and IV doses are ° the same. In many hospitals, these drugs are automatically converted from IV to oral in the same dose by protocol , called a therapeutic interchange or IV to PO protocol , . RxPrep Course Book | RxPrep © 2019 RxPrep © 2020 Bisphosphonates, like ibandronate, have low oral bioavailability, so the oral dose (150 mg PO monthly) must be much higher than the IV dose ( 3 mg IV every 3 months) to produce the therapeutic effect. Bioavailability can be calculated using the area under the plasma concentration time curve, or AUC. The AUC represents the total exposure of drug following administration. Absolute bioavailability, represented by F, is calculated using the following equation: F (%) = 100 x AU Cgxtravascular Dose;intravenous AUCintravenous Doseextravascular L A pharmacokinetic study of an investigational drug was conducted in healthy volunteers. Following an IV bolus dose of 15 mg , the AUC was determined to be 4.2 mg x hr/ L. Subjects were later given an oral dose of 50 mg and the AUC was determined to be 8 mg x hr/ L. Calculate the absolute bioavailability of the investigational drug. Round to the nearest whole number. 8 mg x hr L F (%) = 100 x 4.2 mg x hr L 15 mg = 57% 50 mg Different dosage forms of the same drug (e.g., tablet vs solution ) may have different bioavailabilities. The formula below can be used to calculate an equivalent dose of a drug when the dosage form is changed: Dose of New Dosage Form Amount Absorbed from Current Dosage Form F of New Dosage Form DISTRIBUTION Distribution is the process by which drug molecules move from systemic circulation to the various tissues and organs of the body. Distribution occurs for intravascular and extravascular routes of administration. It depends on the physical and chemical properties of the drug molecule and interactions with membranes and tissues throughout the body. Drugs distribute throughout the body based on the drug's lipophilicity, molecular weight, solubility, ionization status and the extent of protein binding. Factors that favor passage across membranes and greater drug distribution to the tissues include high lipophilicity, low molecular weight, unionized status and low protein binding. Human plasma contains many proteins, and albumin is the primary protein responsible for drug binding. Only the unbound (free ) form of a drug can interact with receptors, exert therapeutic or toxic effects and be cleared from the body. If a drug is highly protein - bound (> 90%) and serum albumin is low (< 3.5 g /dL) , then a higher percentage of the drug will be in the unbound form. Though the unbound form of the drug is responsible for the therapeutic effect, many drug assays cannot differentiate between bound and unbound (active) drug. When assessing levels of highly protein bound compounds (e.g., phenytoin , calcium ) , a patient with low serum albumin has more of the unbound (active ) compound in the serum, and can experience therapeutic or even adverse effects at what appears to be a normal or subtherapeutic drug level. This issue can be overcome by obtaining a "free ” phenytoin level or ionized calcium level. Free phenytoin and ionized calcium only measure the unbound portion, so no adjustment is required for hypoalbuminemia. Otherwise, adjustment of the total level is required. The correction formulas allow us to determine what the concentration would be if albumin was normal. With hypoalbuminemia, the corrected level of a highly protein bound drug will be higher than the total level reported by the lab. This is discussed further in the Calculations III and Seizures / Epilepsy chapters. - l 78 | PHARMAC 0 KINETIC 5 CALCIUM AND PHENYTOIN CORRECTION FORMULAS Ca corrected (mg /dL) = calciumreported (serum ) + [(4.0 - albumin) x (0.8)] t Phenytoin corrected * (mcg/mL) Total phenytoin measured j ( 0.2 x albumin) + 0.1 t Use serum calcium in mg /dL and albumin in g /dL (standard units in the U.S.) in the corrected calcium formula , t Use serum phenytoin in mcg / mL and albumin in g / dL (standard units in the US ) in the corrected phenytoin formula. Same formula is used for valproic acid correction. call from a provider asking for assistance with two patients in the clinic . Both patients have a seizure disorder and are taking phenytoin. Patient A is seizure free, but is experiencing symptoms of toxicity. Patient B has a higher phenytoin level and is doing fine . Both patients have normal renal function. Which of the following statements is/are true of this scenario? (Select ALL that apply. ) 2. A pharmacist receives a LAB REFERENCE RANGE PATIENT A Phenytoin level (total) 10- 20 mcg/mL 14.3 Albumin PATIENT B — 17.8 l 3.5-5 g/dL 2.1 4.2 A. Patient B's corrected phenytoin level will be lower than the total level reported. B. Patient As corrected phenytoin level will be lower than the total level reported. C. Patient As corrected phenytoin level will be higher than the total level reported. D. Patient A has a greater percentage of bound phenytoin. E. Patient A has a greater percentage of unbound phenytoin. The correct answers are ( C and E ) . The corrected phenytoin level for Patient A (using the formula provided ) is 27.5 meg / mL. Increased unbound phenytoin is contributing to the patient s side effects. VOLUME OF DISTRIBUTION The volume of distribution (V or Vd ) is how large an area in the patient's body the drug has distributed into, and is based on the properties of the drug (discussed previously ). The volume of distribution relates the amount of drug in the body to the concentration of the drug measured in plasma (or serum ). When a dose of drug is administered (e.g., 1,000 mg ) , a concentration (e.g., 12 mcg / mL) from a sample of biological fluid can be measured and reported. To convert between amounts and concentrations, a volume is needed. The equation for volume of distribution is: Vd SUBSCRIPTS IN FORMULAS Vd can be written as Vd and ke can be written as ke. Subscripts are not used in this chapter for simplicity. Amount of drug in body Concentration of drug in plasma The Vd is determined from the amount of drug in the body after the dose is given. 3. A 500 mg dose of gentamicin is administered to a patient , and a blood sample is drawn. The concentration of gentamicin is measured as 25 mcg/mL ( which is the same as 25 mg/ L). What is the volume of distribution of gentamicin in this patient? Vd 500 mg 25 mg /L = 20 L Vd is a theoretical value, which is why it is sometimes called the “apparent” volume of distribution. Vd is not an exact physical volume that is measured, but is a helpful parameter used to make inferences regarding how widely a drug distributes throughout the body. 2 RxPrep Course Book | RxPrep 02019, RxPrep 02020 METABOLISM Metabolism is the process by which a drug is converted from its original chemical structure into other forms to facilitate elimination from the body. The original chemical form is called the parent drug and the additional forms are called metabolites. Metabolism can occur throughout the body. The gut and liver are primary sites for drug metabolism due to high levels of metabolic enzymes in these tissues. Blood from the gut travels to the liver before it reaches the rest of the body. First - pass metabolism is the hepatic metabolism of a drug before it reaches the systemic circulation , which can dramatically reduce the bioavailability of an oral formulation. First - pass metabolism of lidocaine is so extensive that the drug cannot be given orally - it must be given IV. Some drugs with extensive first - pass metabolism can be given orally, but in much higher doses than IV doses (e.g., propranolol ). Many non oral, extravascular methods of administration (e.g., transdermal, buccal, sublingual ) bypass First - pass metabolism entirely. About 50% of a drug given rectally bypasses the liver. - Enzyme metabolism involves Phase I reactions (oxidation, reduction and hydrolysis) , followed by Phase II ( conjugation) reactions. Phase I reactions, which can terminate the activity of the drug or convert a prodrug into its active form, provide a reactive functional group on the compound that permits the drug to be attacked by Phase II enzymes. For example, breaking carbon bonds or adding a hydroxyl group to a drug makes the drug more hydrophilic - this means more of the drug stays in the blood, the blood then passes through the kidneys, and the drug is renally excreted. Glucuronidation and other Phase II reactions create compounds that are more readily excreted in the urine and bile. Cytochrome P450 (CYP450) enzymes, located mainly in the liver and intestines, metabolize the majority of drugs. Metabolism is described in detail in the Learning Drug Interactions chapter. EXCRETION Excretion is the process of irreversible removal of drugs from the body. Excretion can occur through the kidneys ( urine ) , liver ( bile), gut (feces) , lungs (exhaled air) and skin (sweat ). The primary route of excretion for most drugs is the kidneys ( renal excretion ). Renal excretion can be increased by adjusting acidity of the urine. For a weak base, increase excretion by acidifying the urine. For a weak acid , increase excretion by alkalinizing the urine. P-glycoprotein ( P- gp) efflux pumps play a role in absorption and excretion of many drugs ( see Learning Drug Interactions chapter ) . Renal excretion is discussed in the Renal Disease and Calculations chapters. CLEARANCE AND AREA UNDER THE CURVE Clearance (Cl ) describes the rate of drug removal in a certain volume of plasma over a certain amount of time. Since the liver and kidneys clear most of the drug (and these organs do not usually speed up or slow down) , most drug elimination occurs at a steady rate (called the rate of elimination ). This is true of drugs that follow first order kinetics (discussed later in the chapter ). The term clearance is used to describe the efficiency of drug removal from the body. Clearance is described by the following equation: Cl Rate of Elimination (Re) Concentration 7 B | PHARMACOKINETICS dose of gentamicin is given to a patient, and urine is collected from the patient for 4 hours after drug administration. It is determined that 300 mg of gentamicin was eliminated during that time period, and the measured plasma concentration at the midpoint of the collection was 12.5 mg/ L. Calculate the patient’s gentamicin clearance. 4. A = Cl 300 mg of gentamicin / 4 hours = 6 L/hr 12.5 mg/L or Cl = 300 mg of gentamicin L x = 6 L /hr 12.5 mg 4 hours The rate of elimination ( Re ) has units of mass per time (e.g., mg/ hr ) , and drug concentration has units of amount per volume (e.g., mg / L); units of mass ( mg) cancel out and clearance has units of volume per time (e.g., L/ hr ). Because the rate of elimination is difficult to assess clinically, another method is used to calculate the clearance of a drug from the body: F x Dose = CIxAUC The area under the curve (AUC) is the most reliable measurement of a drug’s bioavailability because it directly represents the amount of the drug that has reached the systemic circulation . The clearance for extravascular administration is calculated with this formula: F x Dose Cl AUC Following IV administration , bioavailability ( F) = 1, which can be inserted into the previous equation to determine clearance for a drug given intravenously: Dose Cl AUC 5. A patient is currently receiving 400 mg of gentamicin IV once daily and, based on measured serum concentrations, the AUC is determined to be 80 m* xhx/ u Calculate the patients gentamicin clearance. 400 mg Cl 80 mg x hr L 4 = 5 L /hr . RxPrep Course Book | RxPrep © 2019 RxPrep 02020 ZERO VS FIRST ORDER PHARMACOKINETICS Most drugs follow first order elimination or "first order kinetics," where a constant percent of drug is removed per unit of time. For example, a 325 mg dose of acetaminophen is eliminated at the same rate as a 650 mg dose. With zero order elimination, a constant amount of drug ( mg ) is removed per unit of time, no matter how much drug is in the body. The following table provides an example of zero order and first order elimination of a 2 gram dose of a drug. FIRST ORDER ZERO ORDER Hour Amount of Drug (mg) Percent Removed in Previous Hour Amount (mg) Removed in Previous Hour Amount of Drug (mg) Percent Removed in Previous Hour Amount (mg) Removed in Previous Hour 2.000 0 2.000 1 1,700 15 300 1.600 20 400 2 1,400 17.65 300 1,280 20 320 3 1,100 21.43 300 1,024 20 256 MICHAELIS- MENTEN KINETICS Phenytoin , theophylline and voriconazole exhibit MichaelisMenten kinetics (also called saturable, mixed order or non linear kinetics) . The maximum rate of metabolism is defined as the Vmax ( see figure on the right ) . The concentration at which the rate of metabolism is half maximal is defined as the Michaelis-Menten constant ( Km ). At very low concentrations (much less than the Km) , the rate of metabolism mimics a first order process. At most concentrations approaching and exceeding the Km , the rate of metabolism becomes mixed. At even higher concentrations relative to the Km, the rate of metabolism approaches zero order (e.g., Vmax ) . Throughout this process, an increase in dose leads to a disproportionate increase in drug concentration at steady state. The rate of phenytoin metabolism approaches the maximum at accepted therapeutic concentrations. Because of this, phenytoin dose adjustments should be made in small increments (30 - 50 mg ) when the serum concentration is > 7 mcg/ mL. DOSE ADJUSTMENTS FOR MICHAELISMENTEN KINETICS Most drugs follow first order ( linear) kinetics. At steady state , doubling the dose approximately doubles the serum concentration. Some drugs (phenytoin, theophylline and voriconazole) follow Michaelis- Menten (also called non- linear, saturable or mixed order) kinetics. Doubling the dose of these drugs can more than double the serum concentration. Using a proportion to calculate a new dose is not appropriate. Dosing adjustments must be made cautiously to avoid toxicity. H 76 | PHARMACOKINETICS 6. A patient has been using phenytoin 100 mg three times daily. The phenytoin level was drawn and found to be 8.8 mcg/ mL ( reference range 10 - 20 mcg/mL) . The prescriber doubled the dose to 200 mg three times daily. The patient started to slur her words , felt fatigued and returned to the clinic. The level was repeated and found to be 23.7 meg/ mL. Which of the following statements is accurate regarding the most likely reason for the change in phenytoin level? A. B. C. D. E. Phenytoin half - life is reduced at higher doses. Phenytoin volume of distribution increases at higher doses. The patient's serum albumin level likely increased. Phenytoin bioavailability can decrease at higher doses. Phenytoin metabolism can become saturated at higher doses. The correct answer is ( E ). The most likely explanation for the increase in phenytoin level is that when the dose was doubled , the metabolism became partially or completely saturated , and the steady - state level increased dramatically. ELIMINATION RATE CONSTANT The elimination rate constant ( ke) is the fraction of the drug that is eliminated (cleared ) per unit of time. It is calculated from the Vd and the clearance: ke Cl = Vd 7. A drug has the following pharmacokinetic parameters: Vd = 50 liters and Cl = 5,000 mL/hour. Calculate the elimination rate constant of the drug. ke 5 L /hr = 0.1 hr 1 50 L Be certain that the values are converted to units that properly cancel out in the equation . The ke is 0.1 hr 1 ( meaning that 10% of the drug remaining is cleared per hour ). Predicting Drug Concentrations The ke can be used to predict the concentration of a drug at any time ( t ) after the dose using the below calculations. The second formula is derived from the first. c = Ci 2 ke -kt x ln (C, / C, > = t Where Cl = the first or higher drug concentration ( sometimes the peak concentration ) , C2 concentration (at time = t ). E = the base of the natural log. = the second (or lower) drug 8. A patient received a dose of gentamicin. Just after the infusion, it is known that the drug level was 10 mg/ L, and the patient's ke = 0.22 hr 1. Calculate the predicted concentration after 8 hours. ' C2 6 = 22 10 mg /L x e -0- X 8 = 10 mg/L x 0.172 = 1.72 mg /L RxPrep Course Book | RxPrep © 2019, RxPrep © 2020 9. A patient being treated with vancomycin had a supratherapeutic trough of 28 mcg/ mL. If his ke = 0.15 hr 1 , predict how long it will take for the trough to decrease to his goal therapeutic trough (15 mcg/mL). Round to the nearest hour. 0.15 hr i In ( 28 / 15 ) = t = 4.16 hr, or 4 hours HALF- LIFE AND STEADY STATE The time required for the drug concentration (and drug amount ) to decrease by 50% is called the elimination half - life ( t ,J . For example, it takes 5 hours for theophylline concentrations to fall from 16 to 8 mg/ L. The half -life of theophylline is 5 hours. It takes 5 more hours for the drug concentration to fall from 8 mg / L to 4 mg/ L. Half-life is independent of the drug concentration for drugs exhibiting first -order kinetics. Half -life is more clinically meaningful than ke. The half -life of a drug can be calculated from the ke: 0.693 * = t ke The half - life of a drug can be used to calculate the time required for drug washout (complete elimination ) or the time required to achieve steady -state ( refer to the table below). When a fixed dose is administered at regular intervals, the drug accumulates until it reaches steady state where the rate of drug intake equals the rate of drug elimination. The time required to reach steady state depends on the elimination half -life of the drug. It takes -5 half -lives to reach steady state, assuming the drug follows first -order kinetics (described previously) in a one-compartment distribution model ( the drug is rapidly and evenly distributed throughout the body) and no loading dose has been given. Similarly, 5 half -lives are required to eliminate more than 95% of the drug if no additional doses are given. The most clinically useful information is obtained from drug levels collected at steady state. # OF HALFLIVES ELIMINATION (NO ADDITIONAL DOSES GIVEN ) % OF DRUG REMAINING IN THE BODY ACCUMULATION ( MULTIPLE DOSES GIVEN) % OF STEADY- STATE ACHIEVED 1 50 50 2 25 75 3 12.5 87.5 4 6.25 93.8 5 3.13 96.9 10. Tetracycline has a clearance of 7.014 L/hr and a volume of distribution of 105 L. Calculate the half -life of tetracycline (round to the nearest tenth) and the time required for elimination of greater than 95% of the drug from the body. ke = = 7.014 L /hr Cl s Vd 0.693 ke 105 L = The time required is 10.4 hours 0.693 0.0668 hr i x 5 half-lives l = 0.0668 hr - = 10.4 hours = 52 hours 1C 78 | PHARMAC0KINETIC 5 11. The serum concentration of Drug A over time is plotted in the figure below. What is the half - life of Drug A? Serum Cone (mcg / mL ) Time (hours) The drug concentrations can be presented in a figure (as shown ) or in a list. Identify two times ( in hours) where the drug concentration has decreased by half to find the half - life: At 2 hours the concentration is 12 mcg / mL and at 4 hours the concentration is 6 mcg / mL. It takes 2 hours for the concentration to decrease by 50%, so the half - life is 2 hours. 12. A patient was receiving Drug B for 1 week . The drug was held on June 1st due to an elevated serum concentration . Based on the serum concentrations obtained on June 1st after the drug was held ( shown below) , what is the half life of Drug B? TIME CONCENTRATION OF DRUG B 1400 12 mcg/mL 1500 8.5 mcg/mL 1600 6 mcg/ mL 1700 4.3 mcg/mL 1900 2.1 mcg/mL The drug concentration fell by 50% (from 12 mcg / mL to 6 mcg / mL) in 2 hours, so the half - life of Drug B is 2 hours. This is a different way of presenting the same information from the previous problem. 13. A patient receives 200 mg of a drug with a half- life of 5 hours. How much of the drug remains after 10 hours? 10 hours = 2 half- lives 50 mg of the drug remains after 10 hours 200 mg i 100 mg 50% reduction 5 hours IB JL 50 mg 50% reduction 5 hours J RxPrep Course Book | RxPrep © 2019, RxPrep © 2020 LOADING DOSE Administration of a loading dose can be necessary to rapidly achieve therapeutic concentrations of a drug. When the half life of a drug is long relative to the frequency of administration , several doses must be administered before steady state is achieved. 14. A patient will be started on daily oral digoxin for management of atrial fibrillation . The following pharmacokinetic parameters for oral digoxin are known: F = 0.6, Vd = 500 L and Cl = 120 L/day. When would steady state be reached? Round to the nearest day. 120 L /day Cl ke = Vd Steady State = 500 L = 0.24 days 0.693 0.693 ke 0.24 days ~ 2.89 days ' 5 half-lives x 2.89 days = ~ 14 days It is beneficial to administer a loading dose to achieve the targeted levels more quickly in this case. The loading dose can be determined with the following equation: Desired Concentration x Vd Loading Dose F 15. Using the pharmacokinetic parameters provided in the previous question, what oral loading dose of digoxin is appropriate to rapidly achieve a peak concentration of 1.5 mcg/ L? Loading Dose = 1.5 mcg /L x 500 L Desired Concentration x Vd x F 1,250 meg or 1.25 mg 0.6 THERAPEUTIC DRUG MONITORING Some medications are monitored with drug levels to reach dosing goals and avoid toxicity ( see Learning Lab Values & Drug Monitoring chapter ) . If drug levels are too high , toxicity can occur. If drug levels are too low, the patient 's condition might not adequately be treated. To prevent either toxicity or inadequate treatment, an adjustment of the dosing regimen is needed. The peak level is the highest concentration in the blood the drug will reach. The trough level is the lowest concentration the drug will reach in the blood , and is drawn just before the next dose ( or some short time before the dose is due). When adjusting a dosing regimen, changing the dose generally affects the peak , and changing the interval /frequency generally affects the trough. For aminoglycosides, it is usually preferred to extend the dosing interval (i.e., give the dose less often) instead of decreasing the dose, because it maximizes the killing ability of the antibiotic. Therapeutic drug monitoring optimizes drug therapy by enhancing efficacy (e.g., overcoming resistance) and reducing toxicity associated with overdosing or drug accumulation . n