Pharmacokinetics 1: Drug Absorption and Administration Flashcards
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?
A. Aqueous diffusion
B. Lipid diffusion
C. Facilitated diffusion
D. Active transport
E. Endocytosis
Learning objective: describe the main features of facilitated diffusion of drugs across cell membranes. Answer: C
Facilitated diffusion is a carrier mediated transport that can carry across cell membrane compounds too large or too insoluble in lipids to permeate by aqueous or lipid diffusion. Facilitated diffusion is:
- Passive (t 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).
- Saturable (when the number of molecules to be carried exceed the number of carrier molecules the process becomes saturated and therefore is no longer proportional to the concentration gradient).
- Subject to inhibition (competitive inhibition can occur if there is a second ligand which can bind to the carrier)
A, B) These transport systems are passive but do not exhibits selectivity, competition and saturability.
D, E) These are active transport systems.
Which of the following mechanisms for transmembrane transport of drugs is directly proportional to the concentration gradient of the drug and allows transport of small molecules (MW < 100) only?
A. Aqueous diffusion
B. Lipid diffusion
C. Facilitated diffusion
D. Active transport
E. Endocytosis
F. Bulk flow transport
Learning objective: describe the main features of aqueous diffusion of drugs across cell membranes Answer: A
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 diffusion trough protein channels allows the transfer of only small molecules since the pore of the protein channel is narrow.
B, C, D) Lipid diffusion, facilitated diffusion and active transport can allow the transfer of molecules with MW up to about 1500.
E) Endocytosis is an active permeation process that can allows the transfer of very large molecules (> 30000)
F) Bulk flow transport is proportional to the pressure gradient, not to the concentration gradient.
A 34-year-old man recently diagnosed with grand mal epilepsy started a 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)?
A. 1%
B. 24%
C. 50%
D. 76%
E. 99%
Learning objective: describe the main features of lipid diffusion of drugs across cell membranes
Answer: A
The answer can be found using the Henderson-Hasselbalch equation: WEAK ACID: log non-ionized/ionized = pKa - pH
ionized = water soluble
non-ionized = lipid soluble
Which of the following drugs given by oral route will be more ionized in the duodenal lumen (assuming pH = 6.9 in the lumen)?
A. Cytarabine (base, pKa = 4.5)
B. Prazosin (base, pKa = 6.5)
C. Sulfadiazine (acid, pKa = 6.5)
D. Methotrexate (acid, pKa= 4.3)
E. Metronidazole (base, pKa = 2.5)
Learning objective: explain why lipid and water solubility of drugs are related to their pKa and to the pH of the solvent.
Answer: D
The Henderson-Hasselbalch equation predicts that:
1. a weak acid will be more ionized when pKa<ph></ph>
2. a weak base will be more ionized when pKa>pH.
The amount of ionization will be proportional to the magnitude of the difference pH-pKa for an acid, and the difference pKa-pH for a base. The drug can be ranked as follows from the most ionized to the least ionized:
ionization of acid: pH - pKa
ionization of base: pKa - pH
(Acid) Methotrexate: 6.9 - 4.3 = 2.6
(Acid) Sulfadiazine: 6.9 - 6.5 = 0.4
(Base) Prazosin: 6.5 -6.9 = - 0.4
(Base) Cytarabine 4.5 -6.9 = -2.4
(Base) Metronidazole: 2.5 - 6.9 = - 4.4
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?
A. Receptor mediated endocytosis
B. Carrier mediated transport
C. Ion trapping mechanism
D. ATP dependent transport
E. Drug metabolism in the urine
Answer: C
A weak base will be mainly water soluble when the pKa> pH. Therefore when the pH of the medium is decreased (urine more acidic than blood) more drug will be water soluble and will not be reabsorbed into the tubular cells. In other word more drug will be “trapped” in the urine.
A, B, D) These processes are not lipid diffusion.
E) Drug metabolism in the urine is quite unlikely. Moreover the concentration of the drug will decrease, not increase, if the drug is metabolized in the urine.
Which of the following conditions can delay the absorption of orally administered drugs in most cases?
A. A moderate increase in intestinal peristalsis
B. The presence of strong pain
C. The administration of the drug in aqueous solution
D. A large volume of distribution of the drug
E. A very low clearance of the drug
Learning objective: list the main factors affecting the absorption of drugs administered by oral route.
Answer: B
A 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, C) These factors usually speed up the intestinal absorption of drugs.
D, E) The distribution (Vd) and elimination (clearance) of drugs have nothing to do with absorption.
Different methods of drug administration were showed to students during a lab experiment. Which of the following methods of drug administration generally results in the fastest onset of drug effect?
A. Subcutaneous injection
B. Oral administration
C. Transdermal administration
D. Rectal administration
E. Intramuscular injection
Learning objective: relate the routes of administration to the speed and magnitude of drug effect.
Answer: E
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.
A) In general, drugs given SC will be absorbed more slowly than drugs given IM, since the subcutaneous blood flow is lower than the muscle blood flow.
B, C, D) Absorption from these administration routes is generally slow.
Different methods of drug administration were showed 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?
A. Intramuscular
B. Intraarticular
C. Subcutaneous
D. Sublingual
E. Transdermal
Learning objective: describe the main features of intraarticular drug administration
Answer: B
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.
A, C, D, E) All these routes of administrations lead to systemic distribution of the drug.
Which of the following is a reason for a very low (or even absent) oral bioavailability of a drug?
A. The drug is given in aqueous solution
B. The first-pass effect of the drug is large
C. The drug is half-ionized in the intestinal lumen
D. The drug is rapidly excreted by the kidney
E. The drug rapidly leaves the vascular compartment
Learning objective: describe the relationship between oral bioavailability and first pass effect of a drug.
Answer: B
Drugs administered by oral route must pass across the membranes of 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 circulation. If this first pass loss is large the oral bioavailability of the drug could be very low or even absent.
A) The bioavailability of a drug is usually increased, not decreased, if the drug is administered in aqueous solution.
C) If a drug is half-ionized, 50% of the drug will be non-ionized and therefore lipid soluble. This fraction will cross easily the intestinal wall.
D, E) Excretion by the kidney and distribution (leaving the vascular compartment) of drugs have nothing to do with bioavailability.
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)?
A. Rectal
B. Intramuscular
C. Oral
D. Sublingual
E. Subcutaneous
Learning objective: relate the routes of administration to the bioavailability of a drug.
Answer C
A large first pass effect means that a substantial amount of the drug is eliminated (by hepatic metabolism) before reaching the general circulation (presystemic 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 will be low. Since the area-under-curve is a measure of bioavailability this area will be low.
A) The blood from the second and third hemorrhoidal plexus reaches the vena cava without entering the hepatic portal circulation, and drugs absorbed from the rectal mucosa can (at least partially) avoid the first pass effect. Therefore, for drugs with a large first pass effect (like morphine) rectal bioavailability is usually higher that oral bioavailability.
B, D, E) Drugs given by these routes do not go through the liver before entering the systemic circulation and therefore they do not undergo the first pass effect.
The pharmacokinetics properties of five new drugs (P, Q, R, S, T) were studied in healthy volunteers. The same dose of each drugs was administered IV and orally to the same subject on two separate occasions. The results were the following:
Which of the following drugs has most likely the highest oral bioavailability?
A. Drug P
B. Drug Q
C. Drug R
D. Drug S
E. Drug T
Learning objective: calculate the oral bioavailability of a drug, given sufficient data
Answer D
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.
A, B, C, E) (see explanation above)
F (%) = AUC (method) / AUC IV (=1)
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?
A. Cmax
B. CL
C. AUC
D. Vd
E. Tmax
F. t1⁄2
Learning objective: explain the meaning of the “area under the curve (AUC)” of a drug.
Answer C
The area under the curve is used to calculate the bioavailability of a drug after the 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.
A) Cmax indicates the peak blood levels of the drug and therefore it is directly proportional to the dose given. However, it cannot predict the total amount of drug inside the body, since this amount is influenced by the fraction of drug absorbed, which cannot be calculated from Cmax
B) Clearance can only predict the rate of drug elimination.
D) Vd can only predict the extent of drug distribution
E) Tmax can only predict the speed of drug absorption
F) Half-life can predict only the speed of drug elimination.
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?
A. Active transport
B. Lipid diffusion
C. Aqueous diffusion
D. Facilitated diffusion
E. Bulk flow transport
Learning objective: describe the main features of facilitated diffusion of drugs across cell membranes.
Answer: D
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 side of the membrane no net transport will take place. However, since most cells utilize glucose as fuel, the concentration gradient can be maintained. The absorption of glucose from the intestine is different. It is an active secondary transport system (SGLT) which utilize a Na+/glucose cotransporter.
A, B, C, E) (see explanation above)
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? (Check all that apply)
A. It inhibits the enzyme that hydrolyzes angiotensin I
B. Its prolonged use can cause weight gain
C. It is converted by the liver into an active metabolite
D. It can inhibit the secretion of ACTH by the pituitary
Learning objective: explain the meaning of pharmacokinetic properties of a drug”.
Answer C:
- Pharmacokinetics is what the body does to the drug.
- Pharmacodynamics is what the drug does to the body.
The right answer is the option that describe something that the patient’s body is doing to the drug molecule.
A, B, D) These are properties that refer to some actions of the drug, even if these actions can affect the pharmacokinetic of another compound (see angiotensin I) and are, therefore, pharmacodynamic properties.
Which of the following formulas can be used to calculate the oral bioavailability of a drug?
A. AUC oral / Vd
B. AUC oral / AUC IV
C. AUC IV / AUC oral
D. Vd / AUC IV
E. Vd / AUC oral
F. AUC IV / Vd
Learning objective: identify the formula needed to calculate the bioavailability of a d rug.
Answer: B
Bioavailability is determined by administering a dose of drug intravenously (IV) and than 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:
AUC oral / AUC IV.
A, C, D, E, F) (see explanation above)
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?
A. Form P
B. Form Q
C. Form R
D. Form S
E. Form T
Learning objective: -explain why the dosage form of a drug formulation can affect the oral bioavailability of a drug
Answer C
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 portal circulation. The efficiency of this process depends on several factors: the way the tablet is manufactured, the excipients used, etc. Once in the portal circulation the drug can be metabolized by the liver, but the hepatic clearance will be the same, no matter the different dosage forms. Since the same dose of the drug was administered, the oral bioavailability of different dosage forms will be directly proportional to the AUCs depicted in the table. Therefore, the higher the concentration of the drug in the portal vein, the higher the bioavailability of the dosage form.
A, B, C, D) (see explanation above)
