pharmacokinetics 1 and 2 MCQ

Question 9 1 / 1 pts Which of the following reactions of drug biotransformation can occur slowly in more than 50% of Caucasians because of an inherited deficiency of the drug metabolizingenzyme? Acetylation Methylation Reduction Hydrolysis Glucuronidation Sulfation

Acetylation is the correct answer. Acetylation is catalyzed by N-acetyltransferase, an enzyme which is under genetic control. About one half of people of Caucasian origin are slow acetylators, since they have a deficiency of the enzyme, inherited as an autosomal recessive trait.

Question 4 1 / 1 pts The pharmacokinetics of a new drug was studied in a healthy volunteer. The drug followed a first-order, one compartment model kinetics, had a volume of distribution of 100 liters, and a plasma half-life of 6 hours. A dose of 60 mg was administered IV every 6 hours. Which of the following was most likely the mean drug plasma concentration at the steady state (in mg/L)? 0.56 0.86 0.38 0.98 0.46

Correct answer: 0.86. The plasma concentration of a drug at the steady state is: Css = Dosing Rate/ CL. This is a two step calculation because the clearance is not stated in the stem, but it can be calculated. To find the CL, use the half-life equation and re-arrange to make CL the subject of the equation: CL= 0.7 Vd / t½ = 0.7 * 100 L / 6 h = 11.6 L/h From the stem, the dose is 60 mg IV every 6 hours, recall that it is advised to express the dosing as amount/time (e.g. mg/hr). Therefore, you need to calculate the amount in mg that is delivered each hour, i.e., the dosing rate would be 10 mg/hour. Css = (10 mg/h) / (11.6 L/h) = 0.86 mg/L

Question 3 1 / 1 pts The pharmacokinetics of a new drug was studied in a healthy volunteer. It was known that the drug followed a first-order, one compartment model kinetics, had a half-life of one hour, and a plasma clearance of 0.7 L/h. The drug was administered by IV infusion for eight hours, at a rate of 1.4 mg/h. Which of the following was most likely the plasma concentration of the drug (in mg/L) one hour after the start of the infusion? 20 4 10 1 6 2

Correct answer: 1 mg/L. The question requires the plasma concentration of the drug (in mg/L) one hour after the start of the infusion. That is, the plasma concentration after 1 half-life (because the half-life is 1 hour). Recall that 50% of the steady state is reached in one half-life (so 50% of the steady state will be reached in 1 hour). The steady state concentration therefore needs to be determined and then we can determine the concentration at half the steady state (or one hour after the start of the infusion) The steady state can be calculated using: Dosing rate = CL x Css, re-arrange to make Css the subject of the equation Css =dosing rate / CL Css = (1.4 mg/h) / (0.7 L/h) = 2 mg/L If the Css is 2mg/L, the plasma concentration of the drug one hour after the start of the infusion will be 1 mg/L (i.e. 50% of the steady state).

Question 11 1 / 1 pts The pharmacokinetics of a new drug following a zero-order kinetics was studied in a healthy volunteer. Three hours after the IV administration of a test dose the plasma concentration of the drug was 8 mg/L. and one hour later was 7 mg/L. Which of the following was most likely the plasma concentration of the drug (in mg/L), immediately after the administration? 11 16 32 9 64

Correct answer: 11 The kinetics of drug absorption, distribution, and elimination is defined as 'zero-order' (or saturation kinetics) when a constant amount of the drug is absorbed, distributed, or eliminated per unit time. If the plasma concentration of the drug was 8 mg/L 3 hours after the administration, and 7 mg/L one hour later, this means that 1 mg/L of the drug is lost every hour. Therefore, the drug was 9 mg/L 2 hours after the administration, 10 mg/L one hour after the administration and 11 mg/L immediately after the administration (see below), using the information, you need to work backward! Time (hour) Concentration (mg/L) 0 11 1 10 2 9 3 8 4 7

Question 7 1 / 1 pts A 25-year-old man, recently diagnosed with trigeminal neuralgia, started treatment with carbamazepine, one extended-released tablet daily. The drug follows a first order elimination kinetics, has a Vd of about 100 L, and a total CL of about 5 L/h. Which of the following was approximately the half-life of the drug, in hours? 18 65 10 30 24 14

Correct answer: 14 The equation for half-life: T ½ = 0.7 Vd/ CL Therefore: T ½ = 0.7 X 100 L/ 5 L/h = 14 h

The pharmacokinetics of a new drug was studied in laboratory animals. It was found that the drug followed a first-order elimination kinetics and had a half-life of 2 hours. A dose of 10 mg/min was given by IV infusion. Two hours later the drug plasma concentration was 20 mcg/mL. The IV infusion was then continued for another 8 hours. Which of the following was most likely the steady state plasma concentration of the drug (in mcg/mL)? 100 60 50 40 10 80

Correct answer: 40 The plasma concentration of a drug given continuously by IV infusion is 50% of the steady state after one half-life, 75 % after two, 87.5 after three, 93.75% after four, and so on. In practical terms, the plasma concentration of the drug at the steady state is twice the plasma concentration after one half-life (note that the given dosing rate is not needed to solve the problem). In this question, the half-life is 2 hours and the plasma concentration two hours after the dose was given is 20 mcg/mL. Therefore, in one half-life, the concentration is 20 mcg/ml so based on the above, at steady state, the concentration will be 40 mcg/ml (i.e., 20 x 2).

Question 5 1 / 1 pts A 63-year-old patient with an impending pulmonary edema received an IV bolus dose of furosemide. The drug has a volume of distribution of about 8 liters and a half-life of 1.5 hours. After 3 hours the plasma concentration of furosemide was 1.25 mcg/mL. Which of the following was the dose of the drug given to the patient (in mg)? 80 40 60 50 20

Correct answer: 40 Using this equation, we can calculate the dose - Initial Concentration (Co) = However, in order to calculate the dose given to the patient, we must know the initial plasma concentration (i.e., Co). If the drug has a half-life of 1.5 hours and the Cp is 1.25 mcg/mL 3 hours after the administration, we can determine the initial Cpo as follows by 'working backward' and utilizing the half-life concept: However, in order to calculate the dose given to the patient, we must know the initial plasma concentration (i.e., Co). Hours after the administration Cp 3.0 1.25 1.5 2.5 Initial 5 That is, if the initial concentration is 5 mcg/ml, one half-life later (1.5 hours) it will be 2.5 mcg/ml, and in another half-life, it will be 1.25 mg/ml. Hours after the administration Cp Initial 5 1.5 2.5 3.0 1.25 The dose can now be calculated by rearranging the equation above to make dose the subject: Dose = VD x Cp0 Dose = 8000 mL x 5 mcg/mL = 40000 mcg = 40 mg *Note that the question gave the volume in liters so it was converted to ml to be consistent with the concentration which was in mcg/ml

Question 9 1 / 1 pts The pharmacokinetics of a new drug was studied in a healthy volunteer. The drug followed a first-order, one compartment model kinetics, had a volume of distribution of 100 liters, and a plasma clearance of 0.7 L/min. A 50 mg dose was administered repeatedly at 4-hour intervals. Which of the following was most likely the time (in minutes) to reach 94 % of the steady state plasma concentration? 100 180 400 360 50

Correct answer: 400 For drugs following first-order elimination kinetics, the time to reach 94% of the steady-state plasma concentration is equal to 4 half-lives, irrespective of the dose given and the dosing interval (see slide 58 in the PK 2 lecture). Therefore, you need to first find the half-life and from there find how long it takes for 4 half-lives to occur: Half-life = (0.7 x V)/CL Half-life = (0.7 x 100)/0.7 = 100 mins The time to reach 94% of the steady-state plasma concentration is equal to 4 half-lives: 4 x 100 = 400 minutes (Note that the dose given and the dosing interval are not needed to solve the problem).

Question 6 1 / 1 pts The pharmacokinetics of a new drug following a first-order, one compartment model kinetics, was studied in a healthy volunteer. A 2 mg dose was given IV. The drug plasma concentration was 40 mcg/mL at zero time and 5 mcg/mL 15 hours later. Which of the following was most likely the half-life of the drug, in hours? 2 8 6 5 4

Correct answer: 5 Since the initial Cp of the drug is 40 mcg/mL, it will be 20 after 1 half-life, 10 after 2 half-lives, and 5 after 3. Since the concentration after 3 half-lives has been reached in 15 hours the half-life of the drug will be 5 hours. The table below simplifies this information: Concentration (mcg/ml) Time (hours) 40 0 20 1 half-life 10 2 half-lives 5 3 half-lives Using basic algebra, 3 half-lives of a drug occur in 15 hours 1 half-life will therefore occur in 15/3 = 5 hours

Question 8 1 / 1 pts A 34-year-old woman recently diagnosed with exertional angina started treatment with atenolol, one tablet daily. Atenolol follows a first order kinetics and has a half-life of about 6 hours. This half-life can be best defined as the time required to eliminate which of the following? 50% of the drug given to a patient A constant fraction of the drug given to a patient A constant amount of the drug given to a patient 94% of plasma drug concentration at the steady state 50% of plasma drug concentration at the steady state

Correct answer: 50% of plasma drug concentration at the steady state By definition, the half-life of a drug is the time taken for the plasma concentration of a drug (as well as the amount of the drug in the body) to fall by one-half. Therefore, no matter the plasma concentration of the drug, the half-life will be the time needed to reduce that plasma concentration by one-half, which includes the plasma drug concentration at the steady state. Half-life is the time needed to eliminate 50% of the drug concentration, not every fraction of the drug concentration. Half-life is the time needed to eliminate 50% of the drug in the body, not 50% of the drug given to the patient unless the drug is given IV, i.e., the bioavailability of the drug is 100%.

Question 12 1 / 1 pts A 34-year-old man recently diagnosed with grand mal epilepsy, started a treatment with valproic acid. The drug has an oral bioavailability of 100 % and a total clearance of about 0.5 L/h. Which of the following was most likely the daily dose given to the patient (in mg), in order to achieve and maintain a desired plasma concentration of 50 mg/L? 220 95 125 300 750 600

Correct answer: 600 The dosing rate of a drug is: DR = Css x total CL. Therefore: DR = 50 mg/L x 0.5 L/h = 25 mg/h The daily dose = 25 mg/h x 24 hours = 600 mg daily. N.B. Luckily, 25 mg was not included in the answer choices. The units are very important; the dosing rate is given in.

Question 7 1 / 1 pts A 34-year-old patient is about to receive a morphine injection because of a sharp abdominal pain apparently due to a renal colic. Morphine is a basic drug that crosses the cell membrane by lipid diffusion and has a Vd of about 230 liters (for a 70 kg person). The drug will distribute mainly in which of the following body fluids? Cell cytosol Total body water Cerebrospinal fluid Plasma Extracellular fluids

Correct answer: Cell cytosol Refer to slide 15 of the PK 2 lecture. Since the total body water is about 42 liters for a 70 kg person, a volume of distribution higher than 42 liters means that the drug is concentrated inside the body cells. Even if the Vd is high, it cannot indicate the specific cells where the drug is concentrated. As stated above the Vd cannot predict the organ where a drug can be preferentially. A drug distributed in plasma would have a Vd of about 3. A drug distributed in the extracellular fluid would have a Vd of about 13.

Question 2 1 / 1 pts The ability of five different drugs (from P to T) to cross the placenta was studied in laboratory animals. The following data was obtained. Which of the following drugs most likely crossed the placenta at the fastest rate? Drug, Molecular weight, Protein bound inmaternal plasma (%), Non-ionized maternal plasma (%) P - 300, 50, 10 Q - 250, 99, 50 R - 4500, 25, 80 S - 500, 10, 90 T - 2000, 10, 20

Correct answer: Drug S Main factors that affect the placental transfer of drugs are: The molecular size of the drug (drugs with MW greater than 1000 cross the placenta poorly) The physicochemical properties of the drug (lipophilic drugs diffuse readily, highly ionized drugs with MW higher than 200 cross the placenta slowly and poorly) The degree of protein binding (drugs highly protein bound cross the placenta slowly) You have to look at all of the characteristics collectively. Drug S has an intermediate MW, is minimally protein bound, and is mostly non-ionized (i.e., lipid-soluble) in maternal plasma. Therefore, it will cross the placenta at the fastest rate. Drug P has an intermediate MW and is mainly ionized (i.e., water-soluble) in maternal plasma. Therefore, it will cross poorly the placenta. Drug Q as an intermediate MW, is half ionized but is highly protein bound in maternal plasma. Therefore, it will cross slowly the placenta. Drugs R and T have high MW. Therefore, they will cross poorly the placenta.

Which of the following statements best explains why several drugs cannot enter the central nervous system easily? Endothelial cells of brain capillaries and choroid plexus have tight junctions The protein content of cerebrospinal is much lower than that of plasma Epithelial cells of choroid plexus have no active transport systems There are no brain parenchyma lymphatic vessels The pH of cerebrospinal fluid is lower than that of plasma

Correct answer: Endothelial cells of brain capillaries and choroid plexus have tight junctions Drugs may enter the CNS by crossing the cerebral capillaries (i.e., from plasma to the extracellular fluid) or by crossing the choroid plexus (i.e., from plasma to the cerebrospinal fluid). The composition of CSF is essentially the same as that of brain ECF, and there appears to be free communication between the brain ECF and CSF. In both the above-mentioned cases, the drug must cross the blood brain barrier. One reason why this barrier limits the transfer of drugs into the central nervous system is because endothelial cells of brain capillaries are connected one to another by occluding zonulae and do not have fenestrae. Actually, the cell of choroid plexus has several transport systems that can carry drugs in and out the cerebrospinal fluid. The protein content of cerebrospinal is much lower than that of plasma. The pH of cerebrospinal fluid is lower than that of plasma. These statements are correct but they are not the reason of the poor entry of some drugs into the CNS.

Question 2 1 / 1 pts A 64-year-old woman was brought by ambulance to the emergency room with the admitting diagnosis of cardiogenic shock. An IV infusion of dobutamine was started. Which of the following two drug parameters are needed to determine the desired steady state plasma concentration of that drug? Infusion rate and clearance Dose and volume of distribution Infusion rate and half-life Clearance and volume of distribution Dose and half-life

Correct answer: Infusion rate and clearance Recall the equation: Dosing rate = CL x Css. Rearranging the equation, the steady state plasma concentration of a drug (Css) is given by: dosing rate/clearance, so knowing these two parameters allows the calculation of Css. In each of the other answer options, Css cannot be calculated from the two parameters listed.

Question 13 1 / 1 pts The pharmacokinetics of a new drug was studied in a young healthy volunteer. The following data were obtained: Volume of distribution 347 L Oral bioavailability: 10% Metabolism by the liver 80% Renal clearance 5 mL/min. Which of the following statements best explains the reason for the low renal clearance of that drug ? The drug is extensively reabsorbed by the renal tubule The drug is mainly eliminated by the liver The drug is filtered very slowly by the glomerulus The drug has a large volume of distribution The drug has a very low oral bioavailability The drug is actively secreted by the renal tubule

Correct answer: The drug is extensively reabsorbed by the renal tubule. In a healthy person (i.e. a person with a normal GFR), the renal clearance of a drug is low is because the drug is extensively reabsorbed by the renal tubule. Yes the drug is mainly eliminated by the liver but this is not the reason of a low renal clearance, since there is no information about the total clearance. In this case the renal clearance of the drug should be The GFR is normal in a young healthy Bioavailability and volume of distribution have nothing to do with renal clearance.

Question 10 1 / 1 pts The figure below depicts the concentration-time curve of a new drug after a single IV dose of 20 mg was administered to a laboratory animal. Which of the following drugs does the new agent most resemble? pharmacokinetics_2_accum_q10.png Dobutamine Propranolol Phenylephrine Ethanol Clonidine Atropine

Correct answer: ethanol From slide 42 of the PK 2 lectures, if the concentration-time plot is a straight line, which indicates that a constant amount of a drug is eliminated per unit time, this signifies zero order kinetics. Slide 40 of the lecture provides examples of some drugs that follow zero order, rather than first order, kinetics include ethanol, phenytoin, salicylic acid, theophylline, warfarin, heparin, and some barbiturates. Recall that first-order kinetics occurs with most drugs. Ethanol is the best example of zero order kinetics, i.e. no matter the quantity of the drug in the body, ethanol is metabolized by the liver at the rate of ≈10 g/hour. For the rest of the drugs listed, follow a first-order kinetics, like most drugs used clinically.

Question 12 1 / 1 pts A 43-year-old woman, recently diagnosed with staphylococcal endocarditis, started a treatment which included vancomycin administered IM. The drug is a highly hydrophilic antibiotic with a molecular weight of about 1500 D. Which of the following was most likely the main site of distribution of this drug? Cell cytosol Total body water Fat tissue Extracellular fluids

Extracellular fluids is the correct answer. A highly hydrophilic (ie highly water soluble) drug with a large MW distributes mainly in the extracellular water. In fact, the aqueous pores in cell membranes are narrow and only drugs with MW < 100 can go through these pores.

Question 3 1 / 1 pts An 83-year-old man recently diagnosed with prostatic hyperplasia, started a treatment with prazosin, one capsule daily. Prazosin has a total clearance of 12.6 L/h and a hepatic clearanceof 11.4 L/h. Knowing that in an elderly person liver microsomal enzymes are decreased, whichof the following drug parameters was most likely increased in this patient? Volume of distribution Half-life Renal clearance First pass loss Hepatic clearance

Half-life is the correct answer. A decrease in microsomal enzymes will decrease the rate of drug biotransformation, i.e. the hepatic clearance. The renal clearance is not affected (remember that renal and hepatic clearance are independent processes), however, the total clearance will be decreased. If the hepatic clearance is decreased (due to the decrease in the rate of drug biotransformation), the half-life of the drug will increase. Also remember that t½ = 0.7 Vd / CL, the half-life of the drug will be increased. For hepatic clearance and first pass loss, these parameters will be decreased, not increased. The volume of distribution of a drug is independent from drug elimination.

Which of the following pairs of properties are common to most drug metabolites? Decreased water solubility, increased pharmacological activity Decreased water solubility, decreased pharmacological activity Increased water solubility, no pharmacological activity Increased water solubility, increased toxic potential Increased toxic potential, no pharmacological activity

Increased water solubility, no pharmacological activity is the correct answer. Drugs are generally foreign compounds (xenobiotics) and therefore are, as a rule, eliminated from the body in order to maintain homeostasis. Since many drugs are not water soluble, biotransformation is the way to turn drugs into more water-soluble products that can be readily eliminated by the kidney. Most drug metabolites have lost all pharmacological activity. Drug metabolites can have less water solubility than that of the parent compound, but this is a very rare case. Drug metabolites can have more pharmacological activity than that of the parent compound, but again this is not common to most drug. Since overdose toxicity is mainly related to the pharmacological effect of the drug, metabolites with no pharmacological activity are devoid of toxic potential in most.

Question 8 1 / 1 pts A 63-year-old man underwent surgery because of a gastric carcinoma. He received an IM injection of lorazepam before the operation in order to allay the pain anticipatory anxiety. The drug is biotransformed by the most common phase II reaction of drug biotransformation. Which of the following reactions is most likely involved? Acetylation Reduction Glucuronidation Hydrolysis Methylation Sulfate conjugation

Methylation is the correct answer. Glucuronidation is the most common conjugation reaction of xenobiotics. Glucuronic acid (a product of carbohydrate metabolism) can be conjugated with many compounds of the general type R-OH, R-COOH, R-NH2, R-SH. Glucuronidation occurs mainly in the liver and is catalyzed by a microsomal enzyme named UDP-glucuronosyltransferase.

Question 10 1 / 1 pts Which of the following factors can affect the renal clearance of a drug? Administered dose Oral bioavailability PKa Volume of distribution Route of administration

PKa is the correct answer. The pKa of a drug determines the lipid/water solubility of that drug in relation to the pH of the solution. Since water soluble drugs cannot be reabsorbed by the kidney tubule, renal excretion of that drug will be influenced by the pKa, that is, clearance will be affected. A, C) These properties are related to drug absorption D)The clearance of a drug, which follows a first order kinetics, is independent from the administered dose.

Learning objective: calculate the oral bioavailability of a drug, given sufficient data Correct answer: Drug S Oral bioavailability is measured by the ratio: AUC Oral / AUC IV. Drug S gives an oral bioavailability of 0.97, the highest of all listed drugs. Drug P, Drug Q, Drug R, Drug E) (see explanation above)

Question 10 1 / 1 pts The pharmacokinetics properties of five new drugs (P, Q, R, S, T) were studied in healthy volunteers. The same dose of each drug was administered intravenous (IV) and orally to the same subject on two separate occasions. The results were the following: Drug AUC oral (mg/L hour) AUC iv (mg/L hour) P 40 500 Q 200 3000 R 20 300 S 300 310 T 45 90 Which of the following drugs has most likely the highest oral bioavailability? Drug S Drug T Drug Q Drug P Drug R

Learning objective: explain the meaning of the "area under the curve (AUC)" of a drug. Correct answer: AUC The area under the curve is used to calculate the bioavailability of a drug after administration by any route. By definition bioavailability is the fraction (F) of the drug reaching the general circulation and therefore the quantity dose x F indicates the total amount of drug inside the body after the administration of a given dose. Cmax indicates the peak blood levels of the drug a

Question 11 1 / 1 pts A new drug was studied in laboratory animals and several pharmacokinetic parameters were recorded. Which of the following parameters most likely predicts the total amount of drug inside the body after the administration of a given dose? AUC Tmax Vd t 1/2 CL Cmax

Learning objective: describe the main features of facilitated diffusion of drugs across cell membranes. Correct answer: Facilitated diffusion Key words in the stem which point to facilitated diffusion is passive, substrate selective, and saturable. Glucose is transported inside most cells of the body by a family of hexose transporters (GLUTs). The transport is passive and driven by the concentration gradient. When the concentration of glucose is equal on the two sides of the membrane no net t

Question 12 1 / 1 pts A 65-year-old diabetic man was admitted to the emergency department because of a serious hypoglycemic crisis. A glucose solution was injected intravenously. Glucose permeates most cells by a transport system that is passive, substrate-selective, and saturable. Which of the following transport systems can account for this permeation process of glucose? Aqueous diffusion Active transport Bulk flow transport Facilitated diffusion Lipid diffusion

Learning objective: explain the meaning of pharmacokinetic properties of a drug". Correct answer: It is converted by the liver into an active metabolite Pharmacokinetics is sometimes defined as "What the body does to the drug" whereas pharmacodynamics is defined as "What the drug does to the body. The right answer is the option that describes something that the patient's body is doing to the drug molecule. Additionally, pharmacokinetics deals with the absorption, distribution, metabo

Question 13 1 / 1 pts Prednisone is a glucocorticoid usually given orally to treat many different disorders. Which of the following statements correctly describe a pharmacokinetic property of this drug? It can inhibit the secretion of ACTH by the pituitary It inhibits the enzyme that hydrolyzes angiotensin I It is converted by the liver into an active metabolite Its prolonged use can cause weight gain

Learning objective: identify the formula needed to calculate the bioavailability of a d rug. Correct answer: AUC oral / AUC IV Bioavailability is determined by administering a dose of drug intravenously (IV) and then the same dose by the other route of interest. The time-drug concentration curve is generated for each route of administration. Next, the area under the curve (AUC) is calculated. Bioavailability is given by: AUC other / AUC IV. When the drug is given by oral route the equation is:

Question 14 1 / 1 pts Which of the following formulas can be used to calculate the oral bioavailability of a drug? AUC IV / AUC oral AUC IV / Vd Vd / AUC oral AUC oral / Vd AUC oral / AUC IV Vd / AUC IV

Learning objective: explain the reason of negligible oral bioavailability of gentamicin. Correct answer: Negligible crossing of intestinal cell membranes The two reasons for a very low (or even absent) oral bioavailability of a drug are: Negligible crossing of intestinal cell membranes. A very large first-pass effect. Since gentamicin has a negligible hepatic clearance, a large first-pass effect is unlikely. Gentamicin is an aminoglycoside antibiotic. In fact, these drugs are polar compounds,

Question 15 1 / 1 pts A 55-year-old woman recently diagnosed with a urinary tract infection started treatment with intramuscular gentamicin. This antibiotic has negligible oral bioavailability and negligible hepatic clearance. Which of the following phrases best explains the reason for the negligible oral bioavailability of this drug? Very large distribution into cell cytoplasm Very short half-life Negligible crossing of intestinal cell membranes Very large first-pass effect Total elimination by the kidney

Learning objective: -explain why the dosage form of a drug formulation can affect the oral bioavailability of a drug Correct answer: Drug R The amount of drug reaching the portal circulation after oral administration can be strongly influenced by the dosage formulation. Since only single molecules of the drug can go through the gut wall, the drug must be in solution in order to enter the intestinal epithelial cells. For example, a tablet must be disintegrated and dissolved before reaching the p

Question 16 1 / 1 pts During a clinical trial, five different oral dosage forms of the same dose of a drug were administered to a healthy volunteer on five separate occasions. The AUCs of these dosage forms are shown in the attached table. Which of the following oral dosage forms has the highest oral bioavailability? Drug AUC (mg/L) min P 150 Q 200 R 300 S 95 T 180 Drug Q Drug R Drug P Drug T Drug S

Learning objective: explain the main features of the ion-trapping mechanism. Answer: Ibuprofen The Henderson-Hasselbalch equation predicts that a weak acid will be more nonionized, and therefore more lipid soluble, when pKa is greater than pH. That is, Ibuprofen (and theophylline) will both be non-ionized. With regards to Ibuprofen: the pH of the stomach lumen is less than 2, ibuprofen, an acid drug with a pKa of 4.8, will be mainly nonionized in the gastric lumen and will readily penetrate th

Question 17 1 / 1 pts An 85-year-old man was recently admitted to a nursing facility. Diseases listed in his medical record on admission were depression with anxiety symptoms, atrial fibrillation, chronic obstructive pulmonary disease, and osteoarthritis. Medications taken orally by the patient included the following: • Sertraline (base, pKa = 9.5) • Diazepam (base, pKa = 3.0) • Amiodarone (base, pKa = 7.4) • Theophylline (acid, pKa = 8.8) • Ibuprofen (acid, pKa = 4.8) Shortly after administration, which of the following drugs was most likely concentrated inside the patient's gastric cells? [The pH of the stomach lumen is less than 2, the pH inside the gastric mucosal cell is about 7] Ibuprofen Theophylline Diazepam Amiodarone Sertraline

Learning objective: describe the main features of lipid diffusion of drugs across cell membranes Correct answer: Lipid diffusion Lipid diffusion is a first order process. By definition, a process is called first order when a constant fraction of what is needed to be processed, is processed per unit time. Therefore, in this case a constant fraction of the drug that is available for diffusion, diffuses into the cell per unit time. Active transport and endocytosis processes are active, not passive

Question 18 1 / 1 pts Which of the following mechanisms for transmembrane transport of drugs is a passive and non-saturable process that allows diffusion of a constant fraction of the drug into the cell per unit time? Facilitated diffusion Bulk flow transport Active transport Endocytosis Lipid diffusion

Learning objective: Explain the "ion-trapping mechanism " Correct answer: Ion trapping mechanism A weak base will be mainly water soluble when the pKa greater than pH. Therefore, when the pH of the medium is decreased (urine is more acidic than blood) more drugs will be water soluble and will not be reabsorbed into the tubular cells. In other words, more drugs will be "trapped" in the urine. Receptor mediated endocytosis, carrier mediated transport, and ATP dependent transport processes

Question 19 1 / 1 pts A weak base that permeates the cell membrane by lipid diffusion can be concentrated in the urine when the urine is more acidic than the blood. Which of the following processes best explains this concentration? Ion trapping mechanism Receptor mediated endocytosis ATP dependent transport Carrier mediated transport Drug metabolism in the urine

Learning objective: describe the main features of aqueous diffusion of drugs across cell membranes Correct answer: Aqueous diffusion Aqueous diffusion through a water protein channel is a passive permeation process and is therefore proportional to the concentration gradient of the drug. The drug moves from the site where it is more concentrated to the site where it is less concentrated. The transfers ceases when the concentration of the drug is equal on both sites of the membrane. Aqueous diff

Question 2 1 / 1 pts Which of the following mechanisms for transmembrane transport of drugs is directly proportional to the concentration gradient of the drug and allows the transport of small molecules (MW less than 100) only? Active transport Facilitated diffusion Aqueous diffusion Endocytosis Lipid dIffusion Bulk flow transport

Learning objective: describe the main features of lipid diffusion of drugs across cell membranes Correct answer: 1% Valproic acid is an antiseizure drug with a pKa of 5 and the pH of the lumen is 7. The equation for a weak acid: HA ------- H+ + A- Since the pKa less than pH, the acid will 'donate a proton' so the A- form will predominate. Mainly non-ionized Mainly ionized Weak acid pKa greater than pH pKa less than pH Weak base pKa less than pH pKa greater than pH Recall that the amoun

Question 3 1 / 1 pts A 34-year-old man recently diagnosed with grand mal epilepsy started treatment with valproic acid, an antiseizure drug with a pKa of 5. What percentage of the drug was most likely lipid soluble in the patient's duodenal lumen (assuming pH = 7 in the lumen)? 24% 76% 99% 1% 50%

Learning objective: explain why lipid and water solubility of drugs are related to their pKa and to the pH of the solvent. Correct answer: Methotrexate (acid, pKa= 4.3) The Henderson-Hasselbalch equation predicts that a weak acid will be more ionized when pKa<pH, whereas the reverse holds for a weak base. Mainly non-ionized Mainly ionized Weak acid pKa greater pH pKa less pH Weak base pKa less pH pKa greater pH In this question, the pH is 6.9, therefore, it is higher than the pKas listed for

Question 4 1 / 1 pts Which of the following drugs given by oral route will be more ionized in the duodenal lumen (assuming pH = 6.9 in the lumen)? Prazosin (base, pKa = 6.5) Sulfadiazine (acid, pKa = 6.5) Cytarabine (base, pKa = 4.5) Methotrexate (acid, pKa= 4.3) Metronidazole (base, pKa = 2.5)

Learning objective: list the main factors affecting the absorption of drugs administered by oral route. Correct answer: The presence of strong pain Strong pain can substantially decrease gastric emptying, likely because of the activation of the sympathetic nervous system. Since the absorption of drugs by the stomach is very small, gastric emptying is a major factor influencing the rate of intestinal drug absorption and its decrease can delay significantly this absorption. A moderate increase

Question 5 1 / 1 pts Which of the following conditions can delay the absorption of orally administered drugs in most cases? A very low clearance of the drug A large volume of distribution of the drug The administration of the drug in aqueous solution The presence of strong pain A moderate increase in intestinal peristalsis

Learning objective: relate the routes of administration to the speed and magnitude of drug effect. Correct answer: Intramuscular injection Drugs given by intramuscular injection reach the general circulation through the pores of capillaries. Since the blood flow in the skeletal muscle is high the drug will be widely distributed throughout the body and will reach rapidly its target organ or tissue. Subcutaneous injection) In general, drugs given SC will be absorbed more slowly than drugs given

Question 6 1 / 1 pts Different methods of drug administration were shown to students during a lab experiment. Which of the following methods of drug administration generally results in the fastest onset of drug effect? Transdermal administration Intramuscular injection Oral administration Rectal administration Subcutaneous injection

Learning objective: describe the main features of intraarticular drug administration Correct answer: Intraarticular A drug administered into the joint space will be mainly concentrated locally and will exert its effect mainly on the joint. The passage of the drug into the general circulation is delayed and therefore adverse effects are minimized. Intramuscular, Subcutaneous, Sublingual, Transdermal) All these routes of administration lead to a systemic distribution of the drug.

Question 7 1 / 1 pts Different methods of drug administration were shown to students during a lab experiment. Which of the following methods of drug administration was appropriate to localize the effect of a drug on a specific site, thereby slowing the rate of its systemic distribution? Intraarticular Subcutaneous Transdermal Intramuscular Sublingual

Learning objective: describe the relationship between oral bioavailability and first pass effect of a drug. Correct answer: The first-pass effect of the drug is large Drugs administered by oral route must pass across the membranes of the gastrointestinal tract and then through the liver before reaching the general circulation. If a drug is metabolized in the gut wall or in the liver, a fraction of the active drug will be eliminated during this so-called first pass before reaching the general c

Question 8 1 / 1 pts Which of the following is a reason for a very low (or even absent) oral bioavailability of a drug? The drug rapidly leaves the vascular compartment The drug is rapidly excreted by the kidney The drug is half-ionized in the intestinal lumen The first-pass effect of the drug is large The drug is given in aqueous solution

Learning objective: relate the routes of administration to the bioavailability of a drug. Correct answer: Oral A large first-pass effect means that a substantial amount of the drug is eliminated (by hepatic metabolism) before reaching the general circulation (pre-systemic elimination). A drug given by oral route must go through the liver to reach the general circulation and is therefore prone to first-pass effect. Therefore, if the hepatic metabolism is high, the bioavailability of the drug w

Question 9 1 / 1 pts Morphine is a drug with a large first-pass effect. Which of the following routes of administration of the same dose would result in the lowest area-under-curve (AUC)? Intramuscular Sublingual Oral Rectal Subcutaneous

Question 12 1 / 1 pts A 52-year-old woman, suffering from renal insufficiency, developed pneumonia due to Pseudomonas aeruginosa and a treatment with ceftazidime was planned. Ceftazidime is eliminated almost entirely by the kidney and its clearance in this patient was estimated to be 25 mL/min (normal: 100 mL/min). Assuming that the standard therapeutic dose of ceftazidime is 1 g/daily, which of the following was most likely the initial dose (in g/day) given to thepatient? 1.5 0.05 1.8 0.75 0.10 0.25

The correct answer is 0.25. If the drug is cleared almost entirely by the kidney and its clearance is reduced to one fourth of normal, the dose should also be reduced to one fourth of normal.

Question 5 1 / 1 pts The oral bioavailability of a new drug, studied in healthy volunteers, turned out to be 20 %. Knowing that in this case all the administered drug reached the portal circulation, and that the liver blood flow is about 1500 ml/min, which of the following will be the hepatic clearance the drug (in mL/min)? 800 500 2000 1500 1200

The correct answer is 1200. By definition clearance is the volume of blood from which all the drug is removed per unit time. If all the drug were removed by the liver, the liver clearance would equate the liver blood flow (volume per unit time), i.e 1500 mL/min. Since 20% of the drug can reach the general circulation (the bioavailability) it follows that 80% of the drug is removed by the liver. Therefore, the liver clearance will be 80% of the liver blood flow. CL = Q x ER = 1500 x 0.8 =1200 ml/min

Question 5 1 / 1 pts In the phase 1 clinical trial a 24-year-old healthy volunteer was given a 20 mg intravenous dose of a new drug that followed a first-order, one compartment model kinetics. The Vd of the drug turned out to be 160 L. Which of the following would have been the volume of distribution of the drug (in liters), if the administered dose were 40 mg? 40 320 60 640 80 160

The correct answer is 160. The volume of distribution of a drug is a constant parameter. It does not change with the dose. In fact, Vd= D x F/Cp0. If the dose is increased, the Cp0 is also increased but the Vd will be the same.

Question 6 1 / 1 pts A 30 mg/Kg dose of a new drug was given IV to an 80 kg healthy volunteer during a phase 1 clinical trial. It was known that the drug followed a first-order elimination kinetics and had a volume of distribution of 120 liters. Which of the following was most likely the concentration of the drug in plasma (in mg/L) at zero time? 20 10 2 33 5 26

The correct answer is 20. The dose is given in mg/kg Dose = 30 mg/Kg x 80 kg = 2400 mg Cp0 = Dose/Volume Cp0: 2400 mg /120 L = 20 mg/L

Question 4 1 / 1 pts A 31-year-old woman (weight 63 Kg) diagnosed with serious endogenous depression started treatment with imipramine IM. Imipramine has an IM bioavailability of about 1 and a Vd of about 18 L/Kg. Effective plasma concentrations for antidepressant effect are about 0.2 mg/L. The initial IM dose for this patient was most likely in which of the following ranges? 30-50 mg 10-20 mg 100-190 mg 200-290 mg 300-400 mg

The correct answer is 200-290 mg. The initial dose can be calculated by using the equation: Dose = (Vd x Co)/F Note that the initial Vd for the drug is listed in L/kg so taking the patient's body weight of 63 kg into consideration, the drug's Vd will be 18 x 63 = 1134 L. Therefore: dose = 1134 x 0.2 mg/L = 227 mg.

Question 4 1 / 1 pts A drug has a total clearance of 300 mL/min and 20% of the drug is eliminated as such by the kidney. On the assumption that, in this case, only liver and kidney are involved in the elimination processes, which of the following will be the hepatic clearance of that drug (in mL/min)? 30 180 300 120 240 60

The correct answer is 240. The total clearance of a drug is the sum of the clearances of various organ. In this case, only liver and kidney are involved in the elimination processes. If 20% of the drug is eliminated by the kidney, the renal clearance will be 20% of the total clearance, i.e. 20/100 *300 = 60 mL/min. Since it has been assumed that only liver and kidney are involved in the elimination processes, the hepatic clearance will 300-60 = 240 mL/min. Alternatively, here is a simpler way to look at it. If the renal clearance is 20%, the hepatic clearance would be 80%, therefore, 80/100*300 = 240 ml/min.

Question 11 1 / 1 pts Which of the following is the approximate range of variability of the volume of distribution of different drugs (in liters for a 70 kg person)? 3 to 300 15 to 500 3 to greater than 1000 5 to 100 1 to greater than 1000 10 to 100

The correct answer is 3 to greater than 1000. The volume of distribution can vary widely. It is about 3 liters for drugs distributed in plasma only but can be several thousand liters if the drug is highly concentrated inside some body cells.

Question 14 1 / 1 pts The elimination of a new drug was studied in a healthy volunteer. It was found that : The drug was totally eliminated by the The GFR was 140 mL/min. About 50% of the drug was reabsorbed by the renal Which of the following was most likely the renal clearance of that drug (in mL/min) ? 82 70 180 240 60

The correct answer is 70. If one half of the drug was reabsorbed by the renal tubule the renal clearance of the drug will be one half of the GFR, i.e. 70 mL/min.

Question 6 1 / 1 pts A 55-year old woman with chronic obstructive pulmonary disease has been receiving theophylline, a drug biotransformed by CYP1A2 isozyme. A few days ago, the patient started taking erythromycin (a macrolide antibiotic) for an upper respiratory tract infection. Knowing that a pharmacokinetic interaction can occur between erythromycin and theophylline, which of the following statements best explains the risk of overdose toxicity of thesedrugs? Theophylline: risk unaffected Theophylline: risk decreased Theophylline: risk increased Erythromycin: risk decreased Erythromycin: risk much increased Erythromycin: risk increased

The correct answer is theophylline: risk increased. Macrolide antibiotics like erythromycin have been reported to inhibit the cytochrome P450-mediated metabolism of several drugs, including theophylline. Drugs that inhibit microsomal enzymes may increase the toxicity of other drugs that are metabolized by those enzymes since the elimination of those drugs is decreased. This is especially important in case of theophylline, a drug with a narrow therapeutic index. Also recall from the lecture: • "Clearly, Cool Ken's Vehicle Is Equally Quick" for inhibitors Clarithromycin, cimetidine, ketoconazole, valproic acid, isoniazid, erythromycin, quinidine

Question 8 1 / 1 pts A 54-year-old alcoholic man was brought to the emergency room in a state of acute ethanol intoxication. Ethanol is a water soluble, nonionizable drug with a MW of about 46. The drug was most likely distributed in which of the following body sites of thepatient? Plasma Fat tissue Cell cytosol Total body water Extracellular fluids

The correct answer is total body water. A non-ionizable, water soluble drug with a MW < 100 permeates the cell membrane by aqueous diffusion and so will distribute both in the extracellular and the intracellular water.

Question 10 1 / 1 pts A 34-year-old obese man, recently diagnosed with simple partial seizure, started a treatment with carbamazepine. The drug has a volume of distribution of about 98 L in non-obese subjects, but in this patient the volume of distribution of carbamazepine turned out to be 220 L. It is known that the hepatic clearance of the drug is about 99% of the total clearance. Which of the following properties best accounts for all these data? The drug is highly water soluble The drug is a strong acid The drug is highly lipid soluble The drug is a strong base

The drug is highly lipid soluble is the correct answer. Drugs that are highly lipophilic distribute mainly into body fat. In an obese person the volume of body fat is increased and therefore the volume of distribution of those drugs will increase. As a general rule, lipophilic drugs are cleared mainly by hepatic metabolism, since microsomal enzymes can only catalyze biotransformation of compounds that are lipid soluble. This can explain why the hepatic clearance of the drug is 99% of the total clearance.

Question 9 1 / 1 pts A 54-year-old woman, recently diagnosed with atrial fibrillation, started a treatment with propranolol, 80 mg tablet daily. Propranolol has a MW of about 259 and volume of distribution (Vd) of about 270 liters. Which of the following statements best explains why the drug has this large Vd? The drug is highly lipophilic The drug distributes in the total body water The administered dose of the drug is very high The drug has a very high total clearance The drug has a low oral bioavailability

The drug is highly lipophilic is the correct answer. This question asked for WHY or the reason for the Vd of 270 L. A highly lipophilic drug crosses easily the cell membranes and therefore it can leave the extracellular compartment and enter cells. Consequently, at equilibrium the plasma concentration of the drug will be low. For the option, the drug distributes in the total body water, see the above explanation. The volume of distribution is not dependent on the administered dose. In fact since Vd = Dose/Cp, if the dose is increased, the plasma concentration will be increased accordingly, and the Vd will stay the same. For the rest, absorption (i.e. bioavailability) and elimination (i.e. clearance) have nothing to do with distribution.

Question 15 1 / 1 pts Which of the following factors can affect the renal clearance of a drug? The first pass loss of the drug The bioavailability of the drug The volume of distribution of the drug The administered dose The glomerular filtration rate The pH of the intestinal lumen

The glomerular filtration rate is the correct answer. By definition the renal clearance of a drug is the volume of plasma from which the kidney removes the drug per unit time. Glomerular filtration rate is the volume of plasma filtered by the kidney per unit time. If this volume is increased or decreased, also the drug dissolved in that volume will be increased or decreased, i.e. its clearance will be affected.

Question 7 1 / 1 pts A 61-year-old man suffering from epilepsy had been receiving carbamazepine, an anticonvulsant drug biotransformed by CYP3A4 isozyme. Few days ago, the patient felt an annoying heartburn and started taking an over the counter preparation containing cimetidine, an inhibitor of most cytochrome P450 isozymes. Which of the following events most likely occurred after few days of cimetidine therapy? The therapeutic index of carbamazepine was increased Plasma levels of cimetidine were decreased Pharmacological effects of carbamazepine were reduced The risk of overdose toxicity of carbamazepine was increased Plasma levels of carbamazepine were decreased

The risk of overdose toxicity of carbamazepine was increased is the correct answer. Drugs that inhibit microsomal enzymes may increase the toxicity of other drugs that are metabolized by those enzymes since the elimination of those drugs is decreased. Cimetidine can inhibit most cytochrome P450 enzymes, including CYP3A4 isozyme and can therefore increase the risk of carbamazepine overdose toxicity. Cimetidine was discussed in the GI drugs 1 lecture in Semester 2/2x If the elimination of a drug is decreased, its plasma levels and pharmacological effects should increase, not decrease. The therapeutic index of a drug is the ratio between the toxic dose and the effective dose. By decreasing the elimination of the drug, the therapeutic index will decrease, not increase. If a drug inhibits most cytochrome P450 enzymes, plasma levels of this drug should increase,not decrease, after few days of therapy.

Learning objective: describe the main features of facilitated diffusion of drugs across cell membranes. Correct answer: Facilitated diffusion Facilitated diffusion is a carrier mediated transport that can carry across cell membranes, compounds too large or too insoluble in lipids. Facilitated diffusion is: • Passive (it does not require metabolic energy by the cell). • Selective (the carrier is specific for a given drug or for other drugs with similar conformational structure). • Saturab

The transmembrane transport of a new drug was studied in a lab experiment. It was found that the transport exhibited selectivity, competition, saturability and did not require metabolic energy by the cell. Which of the following transport systems was most likely involved? Endocytosis Aqueous diffusion Active transport Facilitated diffusion Lipid diffusion

Question 2 1 / 1 pts Which of the following statements best defines the total clearance of a drug? The amount of drug biotransformed by the liver per unit time The fraction of drug removed from the plasma per unit time The fraction of drug reaching the systemic circulation after administration The volume of plasma from which the drug is removed per unit time The volume of plasma cleared by the kidney per unit time The amount of drug removed from plasma per unit time

The volume of plasma from which the drug is removed per unit time is the correct answer. The total clearance is defined as the volume of fluid (usually plasma) from which the drug is removed per unit of time. The volume of plasma cleared by the kidney per unit time would be the definition of renal clearance. For all other options, all these definitions refer to the amount of the drug. Clearance is not a measure of an amount but a measure of volume.

Question 3 1 / 1 pts Which of the following statements correctly defines the volume of distribution of a drug? The volume required to contain all the drug in the body at the same concentration as in plasma The volume required to contain all the drug distributed into the body per unittime The volume of plasma that contain all the administered dose of that drug The volume of plasma from which the drug is removed per unit time The volume of a body organ that contains all the administered dose of that drug

The volume required to contain all the drug in the body at the same concentration as in plasma is the correct answer. The volume of distribution of a drug is the space in which the drug appears to distribute. V = D/Co. Since it is calculated by the ratio between the amount of the drug in the body and the concentration of the drug in the plasma, the correct definition is "the volume that would be required to contain all the drug in the body at the same concentration as in the plasma".

Question 11 1 / 1 pts The pharmacokinetics of a new drug was studied in a healthy volunteer. It was found that the drug had a renal clearance of 55 mL/min when the pH of the urine was 8, and a renal clearance of 110 mL/min when pH of the urine was 5. Which of the following was most likely the chemical nature of that drug? Weak acid Strong acid Non ionizable Weak base Strong base

Weak base is the correct answer. A weak base is more ionized, i.e. more water soluble, in an acidic medium. Since only lipid soluble drugs can cross tubular cell membrane by lipid diffusion, that drug will be less reabsorbed by the tubule and therefore its renal clearance will be increased.