Primary FRCA Course Paper 02 Pharmacokinetics

Question 1

The rate of drug absorption from the stomach is (true or false):

lower for fentanyl than diclofenac

Answer 1

True. fentanyl is a weak base with a pKa of 8.4 so is almost entirely ionized in the stomach; diclofenac is a weak acid with pKa of 4 and will be largely unionized in the stomach

Question 2

The rate of drug absorption from the stomach is (true or false):

greater for weak acids than weak bases for drugs with a pKa of 6

Answer 2

True

Question 3

The rate of drug absorption from the stomach is (true or false):

increased in the presence of metoclopramide

Answer 3

False. metoclopramide increases gastric emptying, so reduces drug concentration in the stomach, which reduces rate of absorption from the stomach. Overall. Absorption may be increased, especially for basic drugs - but this is not what the question asks

Question 4

The rate of drug absorption from the stomach is (true or false):

always increased by omeprazole

Answer 4

False. The absorption of weak acids in the stomach will be slowed by PPIs

Question 5

The rate of drug absorption from the stomach is (true or false):

less important than absorption from the small intest

Answer 5

True. In general the greater absorptive area of the small bowel accounts for a greater proportion of drug absorption

Question 6

When considering absorption of drugs from the gastrointestinal (GI) tract

fentanyl is better absorbed from the small intestine than the stomach

Answer 6

True. The pH of the small bowel is higher than the stomach, so weak bases are better absorbed

Question 7

When considering absorption of drugs from the gastrointestinal (GI) tract

thiopental cannot be administered through a GI tract route

Answer 7

False. Thiopental can be administered rectally; it is absorbed fairly well

Question 8

When considering absorption of drugs from the gastrointestinal (GI) tract

atracurium cannot be given orally

Answer 8

True. Atracurium is a bis-quaternary molecule that is permanently charge and not absorbed from the GI tract

Question 9

When considering absorption of drugs from the gastrointestinal (GI) tract

Neostigmine is better absorbed than physostigmine

Answer 9

False. Neostigmine is quaternary and charged, physostigmine is a tertiary amine

Question 10

When considering absorption of drugs from the gastrointestinal (GI) tract

Ketoconazole absorption is increased in patients taking omeprazole

Answer 10

False. Ketoconazole is a weak base but is so lipophilic that oral preparations cannot dissolve in hydrophilic gastric juice unless they can be ionized. By increasing gastric pH PPIs reduce the degree of ionization and so the solubility of ketoconazole

Question 11

Which of the following drugs bind more to alpha-1 acid glycoprotein than to albumin

A. diazepam
B. fentanyl
C. phenytoin
D. ibuprofen
E. lidocaine

Answer 11

B & E

In general acidic/neutral drugs bind to albumin and basic drugs or those with a quaternary nitrogen, to alpha-1 acid glycoprotein. Lidocaine and fentanyl are basic drugs, ibuprofen is acidic and diazepam/phenytoin are neutral - they are not water soluble

Question 12

Which of the following are true of plasma protein binding of therapeutic drugs

displacement of protein-bound drug by a second drug will necessarily cause toxic effects

Answer 12

False. Toxic effects seen only if the therapeutic ratio is small and hepatic extractio ratio is very low

Question 13

Which of the following are true of plasma protein binding of therapeutic drugs

drugs with a low hepatic extraction ratio and high degree of protein binding are most affected by changes in protein binding

Answer 13

True

Question 14

Which of the following are true of plasma protein binding of therapeutic drugs

drugs that show flow-dependent hepatic extraction are unaffected by changes in protein binding

Answer 14

True

Question 15

Which of the following are true of plasma protein binding of therapeutic drugs

the interaction between amiodarone and warfarin is entirely due to competition for plasma protein binding sites

Answer 15

False. This interaction is mainly due to a metabolic interaction: amiodarone inhibits CYP2C9

Question 16

Which of the following are true of plasma protein binding of therapeutic drugs

the renal filtration rate of a drug is increased when plasma protein binding is decreased

Answer 16

True

Question 17

Regarding the distribution of drugs through the body

the volume of distribution at steady state for a drug is dependent only on its lipid solubility

Answer 17

False. although lipid soluble drugs can have very large volumes of distribution, if a drug is rapidly metabolized then it will have a much smaller volume of distribution that might be expected from its lipid characteristics : eg remifentanil

Question 18

Regarding the distribution of drugs through the body

in a one-compartment model, volume of distribution is directly proportional to drug clearance

Answer 18

True. volume of distribution is given by clearance divided by rate constant for elimination (Vd = Cl/k)

Question 19

Regarding the distribution of drugs through the body

drugs with greater than 95% protein binding have a relatively small volume of distribuition

Answer 19

False. propofol has a very large volume of distribution but also is greater than 98% bound - so this is clearly untrue

Question 20

Regarding the distribution of drugs through the body

volume of distribution at steady state is approximately equal to total body water for most drugs

Answer 20

False. volume of distribution varies greatly between drugs: large for propofol, small for atracurium

Question 21

Regarding the distribution of drugs through the body

non-depolarizing muscle relaxants have a smaller volume of distribution than induction agents

Answer 21

True. ndmrs are charged molecules and do not cross lipid membranes so have relatively small volumes of distribution

Question 22

Which of the following describe the distribution of propofol

it has a volume of distribution of approximately 1.4 L/kg

Answer 22

False. Its Vd at steady state has variously been estimated to be as high as 20-60 L/kg, but lower values are found for short infusions. However, in general it has a volume of distribution of at least 4 L/kg

Question 23

Which of the following describe the distribution of propofol

it is an acidic drug so binds to albumin in plasma

Answer 23

True

Question 24

Which of the following describe the distribution of propofol

the volume of distribution is very large as it is essentially unionized at plasma pH

Answer 24

True

Question 25

Which of the following describe the distribution of propofol the initial volume of distribution in adults is age-dependent

Answer 25

False. None of the kinetic models identify age as an independent variable for predicting initial Vd

Question 26

Which of the following describe the distribution of propofol the volume of distribution is high because propofol is highly protein-bound

Answer 26

False. Vd is high because it is extremely lipid soluble and essentially unionized

Question 27

The following are metabolites of atracurium cisatracurium

Answer 27

False. this is just one of the 10 isomers of atracurium, not a metabolite

Question 28

The following are metabolites of atracurium desmethylatracurium

Answer 28

False

Question 29

The following are metabolites of atracurium laudanosine

Answer 29

True. a product of the minor (Hofmann) metabolic pathway

Question 30

The following are metabolites of atracurium 3,17-dihydroxy atracurium

Answer 30

False. the aminosteroids are broken down by deacetylation at the 3 and 17 positions

Question 31

The following are metabolites of atracurium a monoquaternary alcohol derivative

Answer 31

True. a product of the major (ester hydrolysis) pathway

Question 32

Which of the following enzymes demonstrate important pharmacogenetic variation A. CYP2E1 B. CYP2D6 C. CYP3A5 D. CYP2C9 E. CYP1A2

Answer 32

B & D CYP2D6 - This is responsible for codeine conversion to morphine. 10% of Caucasians are poor metabolizers CYP2C9 - This is responsible for the metabolism of S-warfarin

Question 33

Which of the following drugs have an oral bioavailability of more than 75% A. aspirin B. paracetamol C. oramorph D. diclofenac E. ibuprofen

Answer 33

A. False. about 65% B. True. about 90% C. False. about 25% D. False. about 50% E. True. more than 80%

Question 34

The following routes of elimination are the major route for the named drug lungs: sevoflurane

Answer 34

True. >95% excreted unchanged

Question 35

The following routes of elimination are the major route for the named drug renal: benzylpenicillin

Answer 35

True. rapid excretion by tubular secretion

Question 36

The following routes of elimination are the major route for the named drug red cell esterases: esmolol

Answer 36

True

Question 37

The following routes of elimination are the major route for the named drug tissue esterases: remifentanil

Answer 37

True. plasma esterase activity also contributes, but tissue (especially muscle) esterases are most important

Question 38

The following routes of elimination are the major route for the named drug non-enzymic plasma degradation: mivacurium

Answer 38

False. mivacurium is broken down by butyrylcholinesterase, cisatracurium and atracurium are degraded by the Hofmann process

Question 39

In a one-compartment model for the kinetics of a drug if volume of distribution stays the same, clearance increases if the time constant decreases

Answer 39

True

Question 40

In a one-compartment model for the kinetics of a drug the volume of distribution at steady state can be calculated using a single bolus dose of drug

Answer 40

True. There is just one volume to consider

Question 41

In a one-compartment model for the kinetics of a drug the context sensitive half time is proportional to the duration of an infusion

Answer 41

False. the CSHT is always constant and equal to the half-life

Question 42

In a one-compartment model for the kinetics of a drug after giving an intravenous bolus dose, the rate of elimination at a particular time is dependent only on the clearance

Answer 42

False. it is proportional to plasma concentration - an exponential relationship - whereas clearance is constant

Question 43

In a one-compartment model for the kinetics of a drug the behaviour of the drug can be predicted as long as the clearance is known

Answer 43

False. you need two parameters to describe the behaviour of the drug: volume of distribution and time constant (or rate constant for elimination). Clearance simple gives you the ratio of these two values To describe behaviour completely, you need to know both parameters individually, not just the ratio

Question 44

If a drug given by continuous intravenous infusion behaves according to a three-compartment model the volume of distribution at steady state is the most important determinant of the variability of the context sensitive half time

Answer 44

False. the duration of the infusion and the ratio of elimination to redistribution rather than Vdss are most important: if elimination is very rapid and redistribution from compartments 2 and 3 is slow, then CSHT will not vary as much as if elimination were rapid and redistribution also rapid

Question 45

If a drug given by continuous intravenous infusion behaves according to a three-compartment model the second compartment has three rate constants associated with it

Answer 45

False. elimination occurs only from the first (central) compartment, so there are just two: k12 and k21

Question 46

If a drug given by continuous intravenous infusion behaves according to a three-compartment model if the plasma level has reached steady state, then clearance out of the body can be calculated from the infusion rate and concentration

Answer 46

True

Question 47

If a drug given by continuous intravenous infusion behaves according to a three-compartment model drug can be removed from the system from any of the three compartments

Answer 47

False. in the 3-C model, we adopt a mammilary, not a catenary model; elimination is allowed only from the central compartment

Question 48

If a drug given by continuous intravenous infusion behaves according to a three-compartment model the effect compartment equilibrates with the central compartment

Answer 48

True

Question 49

When considering elimination of drug from the body the rate of elimination is equal to the clearance

Answer 49

False. rate of elimination = clearance multiplied by drug concentration

Question 50

When considering elimination of drug from the body if glomerular filtration rate doubles, then the amount of free drug excreted through the urine also doubles

Answer 50

False. urinary elimination depends also on tubular secretion

Question 51

When considering elimination of drug from the body CYP450 enzymes are found only in hepatocytes

Answer 51

False. CYP450 enzymes are expressed in many tissues

Question 52

When considering elimination of drug from the body hepatic enzymes involved in xenobiotic metabolism are exclusively associated with the smooth endoplasmic reticulum

Answer 52

False. there are CYP enzymes in the SER, but metabolic enzymes are also found in the cytoplasm (alcohol dehydrogenase) and associated with mitochondria (MAO)

Question 53

When considering elimination of drug from the body more than 99% of the drug will have been eliminated after three half-lives

Answer 53

False. after 5 half-lives or 3 time constants

Question 54

For a simple one-compartment model the half-life is longer than the time constant

Answer 54

False. the time constant is always longer than the half-life

Question 55

For a simple one-compartment model the rate constant for elimination is found from the slope of the graph that plots log(concentration) against time

Answer 55

True

Question 56

For a simple one-compartment model clearance is the ratio of the volume of distribution to the time constant

Answer 56

True. Clearance = Vd/tau = Vd x k, where tau is the time constant and k the rate constant for elimination

Question 57

For a simple one-compartment model the volume of distribution multiplied by the rate constant for elimination divided by plasma concentration is equal to the clearance

Answer 57

False. this is the rate of elimination. Rate of elimination (k) = Concentration (mg/ml) x clearance (ml/min) Clearance = Vd x k

Question 58

For a simple one-compartment model the shape of the curve that describes the rise of drug concentration with time on starting a constant rate infusion is a negative exponential

Answer 58

True. wash-in curves are negative exponentials because the rate at which concentration changes decreases with time [ Css(1 - exp(-kt))]

Question 59

In patients with hepatic failure and acsites the volume of distribution for hydrophilic drugs is reduced

Answer 59

False. In general Vd increases with ascites

Question 60

In patients with hepatic failure and acsites the metabolism of all drugs is reduced

Answer 60

False. many drugs are affected, but not all

Question 61

In patients with hepatic failure and acsites the bioavailability of drugs with a moderate heptic extraction ratio is increased

Answer 61

True. metabolic capacity will be reduced as may hepatic flow, so it is likely that bioavailability will be increased

Question 62

In patients with hepatic failure and acsites the terminal elimination half-life for remifentanil is unaffected

Answer 62

True

Question 63

In patients with hepatic failure and acsites the dose of non-depolarizing muscle relaxants required for intubation is increased

Answer 63

True. Maintenance doses may need reducing, but the increased initial Vd means a larger initial dose may be needed

Question 64

Which of the following will increase hepatic extraction of propofol. Explain why for each. A. dobutamine B. ciprofloxacin C. carbamezepine D. noradrenaline E. chronic alcohol intake

Answer 64

A only, as it increases hepatic blood flow B. False. ciprofloxacin inhibits CYP1A2, not those enzymes primarily responsible for propofol metabolism (CYP2B6 and CYP2C9). Though they may interact to produce QT prolongation C. False. CYP inducer, but hepatic ER already approaches 1 D. False. cardiac output not necessarily increased, so hepatic flow not increased E. False. propofol is not metabolized by CYP2E1

Question 65

A mammilary three-compartment model used to model effect-site targeting of drug concentration elimination occurs from the effect site

Answer 65

False. The effect site is considered to have a negligible volume and so elimination from this compartment is not a part of the 3-C model

Question 66

A mammilary three-compartment model used to model effect-site targeting of drug concentration the volume of the effect site is not included in the volume of distribution at steady state

Answer 66

True

Question 67

A mammilary three-compartment model used to model effect-site targeting of drug concentration there are two inter-compartmental clearances included in the model

Answer 67

True. In a 3-C model there are three clearances to consider: two inter-compartment clearances and one out-of-system (body) clearance

Question 68

A mammilary three-compartment model used to model effect-site targeting of drug concentration the t1/2keo describes the rate of equilibration between plasma and effect compartments

Answer 68

True. This parameter describes the lag between plasma concentration changes and effect compartment changes

Question 69

A mammilary three-compartment model used to model effect-site targeting of drug concentration clearance from the system can be found from steady-state infusion rate and plasma concentration

Answer 69

True. Input = output principle applies for steady state infusions - the difficulty lies with knowing when steady-state has been reached

Question 70

When measuring bioavailability drug behaviour must be fitted to a known model in order to calculate bioavailability

Answer 70

False. A non-model-based method is used: AUC(oral)/AUC(IV) if looking at oral bioavailability

Question 71

When measuring bioavailability bioavailability refers only to oral compared with intravenous administration

Answer 71

False. Any route can be assessed for bioavailability compared with the standard route of administration (usually IV)

Question 72

When measuring bioavailability oral bioavailability can be found by dividing clearance of the drug when given orally by the clearance found when given IV

Answer 72

False. Clearance should be the same for a drug whether it is given orally or intravenously: bioavailability is the ratio of the area under the concentration-time curve (AUC) for the oral route divided by the AUC for the IV route

Question 73

When measuring bioavailability the same dose of drug must be given orally and intravenously to find oral bioavailability

Answer 73

True

Question 74

When measuring bioavailability interindividual variability must be expected

Answer 74

True. Bioavailability of a given drug for a particular patient will differ depending on many factors including health problems and concurrent medication

Question 75

Which of the listed drugs have a volume of distribution at steady state greater than total body water A. cisatracurium B. neostigmine C. atropine D. noradrenaline E. sevoflurane

Answer 75

C & E. Permanently charged molecules do not distribute across lipid membranes so the muscle relaxants and neostigmine have small volumes of distribution. Atropine and sevoflurane are very lipid soluble and will distribute into lipid areas. Noradrenaline is ionized at body pH and modeling is consistent with rapid metabolism so calculated Vd is small

Question 76

Which of the following drugs readily cross the placenta A. S-bupivacaine B. diazepam C. fentanyl D. succinylcholine E. isoflurane

Answer 76

All except D. Lipid soluble drugs cross the placenta more rapidly than drugs that are ionized at plasma pH; permanently charged drugs do not cross the placenta so muscle relaxants will not affect the fetus