Pharmacokinetics 1 - Drug Distribution Flashcards
Which of the following statements best explains why several drugs cannot enter easily the central nervous system?
A. Epithelial cells of choroid plexus have no active transport systems
B. The protein content of cerebrospinal is much lower than that of plasma
C. The pH of cerebrospinal fluid is lower than that of plasma
D. Endothelial cells of brain capillaries and choroid plexus have tight junctions
E. There are no brain parenchyma lymphatic vessels
Learning objective: explain how the blood-brain barrier can affect the drug distribution into the central nervous system
Answer: D
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 drug 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.
A) Actually, the cell of choroid plexus has several transport systems that can carry drugs in and out the cerebrospinal fluid.
B, C) these statements are correct but they are not the reason of the poor entry of some drugs into the CNS.
The ability of five different drugs (from P to T) to cross the placenta was studied in laboratory animals. The following data were obtained.
Which of the following drugs most likely crossed the placenta at the fastest rate?
A. Drug P
B. Drug Q
C. Drug R
D. Drug T
E. Drug S
Learning objective: describe the factors that facilitate placental crossing of drugs.
Answer: E
Main factors that affect placental transfer of drugs are:
1) The molecular size of the drug (drugs with MW greater than 1000 cross the placenta poorly)
2) The physicochemical properties of the drug (lipophilic drugs diffuse readily, highly ionized drugs with MW higher than 200 cross the placenta slowly and poorly)
3) The degree of protein binding (drugs highly protein bound cross the placenta slowly)
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.
A) Drug P has an intermediate MW and is mainly ionized (i.e. water soluble) in maternal plasma. Therefore, it will cross poorly the placenta.
B) Drug Q as an intermediate MW, is half ionized but is highly protein bound in maternal plasma. Therefore, it will cross slowly the placenta.
C, E) Drugs R and T have high MW. Therefore, they will cross poorly the placenta
Which of the following statements correctly defines the volume of distribution of a drug?
A. The volume of plasma from which the drug is removed per unit time
B. The volume of plasma that contain all the administered dose of that drug
C. The volume required to contain all the drug in the body at the same concentration as in plasma
D. The volume of a body organ that contains all the administered dose of that drug
E. The volume required to contain all the drug distributed into the body per unit time
Learning objective: define the “volume of distribution of a drug”.
Answer: C
The volume of distribution of a drug is the space in which the drug appears to distribute. 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”.
A, B, D, E) (see explanation above)
A 31-year-old woman (weight 63 Kg) diagnosed with serious endogenous depression started a 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?
A. 10-20 mg
B. 30-50 mg
C. 100-190 mg
D. 200-290 mg
E. 300-400 mg
Learning objective: calculate the dose needed to obtain an initial target plasma concentration of a drug, given sufficient data.
Answer D
The initial dose can be calculated by:
Dose = (Vd x C0) /F
The Vd in this patient will be: Vd 18 x 63 = 1134
Therefore: dose = 1134 x 0.2 mg/L = 227
A, B, C, E) (see explanation above)
In a 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?
A. 40
B. 80
C. 320
D. 160
E. 640
F. 60
Learning objective: calculate the Vd of a drug, given sufficient data.
Answer: D
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 and therefore the Vd will be the same.
A, B, C, E, F). (see explanation above)
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?
A. 20
B. 5
C. 10
D. 2
E. 26
F. 33
Learning objective: calculate the initial plasma concentration of a drug, given sufficient data.
Answer: A
The dose given will be 30 mg/Kg x 80 kg = 2400 mg.
The Cp0 will be: 2400 mg /120 L = 20 mg7L
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?
A. Cerebrospinal fluid
B. Plasma
C. Extracellular fluids
D. Cell cytosol
E. Total body water
Learning objective: explain why the Vd can predict to a certain extent the pattern of distribution of a drug in the body.
Answer: D
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 high Vd cannot indicate the specific cells where the drug is concentrated.
A) As stated above the Vd cannot predict the organ where a drug can be preferentially distributed. In fact even if morphine the primary site of action of morphine is the CNS, only small quantities of the drug cross the blood brain barrier.
B) A drug distributed in plasma would have a Vd of about 3 liters.
C) A drug distributed in the extracellular fluid would have a Vd of about 13 liters.
E) (see explanation above)
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 the patient?
A. Fat tissue
B. Plasma
C. Extracellular fluids
D. Cell cytosol
E. Total body water
Learning objective: explain why the Vd can predict to a certain extent the pattern of the distribution of a drug in the body.
Answer: E
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.
A, B, C, D) (see explanation above)
During a phase 1 clinical trial a 30 mg/Kg dose of a new drug was given IV to an 80 Kg healthy volunteer. 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 is most likely the plasma concentration of the drug (in mg/L) at zero time?
A. 2
B. 5
C. 10
D. 20
E. 26
F. 33
Learning objective: calculate the initial plasma concentration of a drug, given sufficient data.
Answer: D
The dose given will be: 30 mg/Kg x 80 kg = 2400 mg.
The Cp0 will be: 2400 mg /120 L = 20 mg/L
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?
A. The drug is highly lipophilic
B. The drug distributes in the total body water
C. The administered dose of the drug is very high
D. The drug has a low oral bioavailability
E. The drug has a very high total clearance
Learning objective: list the main drug factors affecting the Vd of a drug.
Answer: A
A highly lipophilic drug crosses easily the cell membranes and therefore it can leave the extracellular compartment and enter cells. As a consequence, at equilibrium the plasma concentration of the drug will be low. Since Vd = Dose/Cp and the dose is already a predetermined amount, the Vd will be high.
B) If the drug is distributed in the total body water its Vd would be about 42 liters.
C) The volume of distribution is not dependent on the administered dose. In fact since Vd = Dose/Cp, it is clear that if the dose is increased, the plasma concentration will be increased accordingly, and the Vd will stay the same.
D, E) Absorption (i.e. bioavailability) and elimination (i.e. clearance) have nothing to do with distribution.
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?
A. The drug is highly water soluble
B. The drug is highly lipid soluble
C. The drug is a strong acid
D. The drug is a strong base
E. The drug is nonionizable
Learning objective: describe the factors that can explain the high Vd of a drug.
Answer: B
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.
A, C, D, E. F) (see explanation above)
The pharmacokinetics of a new drug that followed first order, one compartment model kinetics, was studied in healthy subjects. It was found that the oral bioavailability of the drug was 0.5. When a 200 mg dose was given orally, the estimated time-plasma concentration curve was the one depicted below.
Which if the following was most likely the volume of distribution of that drug, in liters?
A. 20
B. 35
C. 8
D. 10
E. 5
F. 16
Learning objective: calculate the volume of distribution of a drug, given sufficient data.
Answer: D
The volume of distribution of a drug can be calculated by the formula: Vd= D x F / Cp0
The bioavailability and the dose are known.
The plasma concentration at zero time (Cp0).can be calculated from the picture and is indicated by the intersection point obtained by extrapolating the declining portion of the time-concentration curve (that depicts the elimination phase) to the ordinate is (Cp0).This is because the model assumes that the drug distribute immediately into the one compartment.
In the present case the intersection point is 10 mg / L Therefore: Vd = D x F / Cp0 = 200 mg x 0.5/ 10 mg / L = 10 L
A, B, C, E, F) (see explanation above)
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)?
A. 3 to greater than 1000
B. 10 to 100
C. 5 to 100
D. 15 to 500
E. 1 to greater than 1000
F. 3 to 300
Learning objective: define the range of variability of the Vd of different drugs.
Answer: A
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.
B, C, D, E, F) (see explanation above)
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?
A. Total body water
B. Extracellular fluids
C. Cell cytosol
D. Plasma
E. Fat tissue
Learning objective: explain why the Vd can predict to a certain extent the pattern of distribution of a drug in the body.
Answer: B
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.
A, C, D, E) (see explanation above)
Placental permeability to drugs is variable during pregnancy. The highest permeability occurs during which of the following periods?
A. First week
B. Second week
C. Second month
D. Second trimester
E. Third trimester
Learning objective: identify the pregnancy period of the highest drug permeability of placenta.
Answer: E
The membranes separating fetal capillary blood from maternal blood in the intervillous space resemble cell membranes elsewhere in their general permeability behavior. It is known that the tissue layers between the fetal capillaries and maternal blood become progressively thinner, and so the permeability of placenta to drugs is the highest during the third trimester of pregnancy.
A, B, C, D) (see explanation above).
