Kinetics Exam 4

Which of the following statements regarding protein binding is false?

A. Protein surfaces are mostly hydrophilic with hydrophobic crevices
B. There is a high protein content in the blood plasma
C. Protein binding results in non-uniform distribution of the drug, affecting Vd
D. A hydrophobic drug is unable to bind to protein

Answer: D

Explanation: A hydrophobic drug can easily bind to plasma protein, even if it is highly ionized.

Hydrophilic drugs can also bind to plasma proteins

True/False: Binding can occur in both the tissues and proteins

Answer: True

Explanation: Binding can occur in proteins in both the tissue and plasma as well as nucleotides, ligands, and ATP in the tissues

Which type of binding often leads to toxicity?

A. Irreversible
B. Reversible

Answer: A

Explanation: You know. Despite this, most binding is reversible drug-plasma protein binding

True/False: Clinical labs report total plasma [bound + unbound] as plasma [drug]

Answer: True

Explanation: The majority of drug molecules in plasma are bound to plasma proteins. Free drug molecules are pharmacologically active and in equilibrium with bound drug. It's difficult to ascertain free and bound drug.

Which of the following does not describe bound drug?

A. Cannot easily pass through membranes
B. Has restrictive drug distribution/elimination
C. Therapeutically active
D. None of the above

Answer: C

Explanation: Bound drug is therapeutically inactive.

Unbound drug can cross cell membranes, has unrestricted distribution, and is therapeutically active.

True/False: Typically, a small Vd should result in a small t1/2

Answer: True

Explanation: This is true unless there is high protein binding.

Which of the following plasma proteins binds acidic and basic drugs like salicylates, penicillins, and phenytoin?

A. Albumin
B. AAGP
C. Lipoproteins
D. Protein Powder, get those gains

Answer: A

Explanation: AAGP binds only basic drugs, while lipoproteins bind lipophilic drugs

Which of the following constants measures unbound drug in the plasma?

A. Fu
B. Fut
C. Fe
D. Fm

Answer: A

Explanation: Fut is the fraction of unbound drug in tissue. Fe is fraction of drug eliminated unchanged in the urine. Fm is the fraction of drug metabolized.

Fu = [unbound] / ([bound] + [unbound])

True/False: Vd = Vp + Vt(Fu / Fut)

Answer: True

Explanation: Vp is plasma volume, while Vt is tissue volume.

This describes the physiological model

True/False: Fu stays constant as Cp increases for drugs bound to albumin until very high plasma concentrations

Answer: True

Explanation: The number of protein binding sites on albumin is much greater than drug molecules to take them. However, at very high Cp, binding sites are saturated, so Fu increases as Cp increases

True/False: Highly bound drugs (which have a low Fu) typically have a high Vd

Answer: False

Explanation: These typically have a low Vd (refer to the equation to calculate Vd)

True/False: As Vd increases, Cp decreases in response

Answer: True

Explanation: More drug is in the tissue, decreasing plasma concentrations

True/False: Drugs that are subject to restrictive elimination, in cases where fu increases, the increase in unbound drug is sometimes cancelled out by increased elimination

Answer: True

Explanation: This can sometimes occur. If it happens, drug effect is not altered.

True/False: A strongly protein bound drug needs a larger dose to have a therapeutic effect

Answer: True

Explanation: We measure this with the Affinity constant, Ka. A high Ka means strongly protein bound drugs.

Drug affinity can also be altered in the case of uremia.

I would look at the graph on slide 43 to better understand this

Which of the following statements regarding drug protein binding is false?

A. Any factor that alters protein binding becomes highly clinically important when a drug is highly protein bound (fu < 0.1)
B. Decreased albumin occurs in hepatic failure, renal failure, burns, stress/trauma, and pregnancy
C. Decreased AAGP occurs in MI, renal failure, arthritis, and surgery
D. Decreased Tissue binding affinity occurs in uremia

Answer: C

Explanation: You see increased AAGP in MI, renal failure, arthritis, and surgery.

Also, with decreased tissue binding affinity in uremia, the effect may be transient

True/False: Displacers achieve high concentrations in either the plasma or tissues, displacing drugs from either plasma proteins or tissue sites

Answer: True

True/False: Generally, in biotransformation, lipid-soluble drug is chemically modified to water-soluble metabolites that are more readily excreted

Answer: True

Which of the following phases of biotransformation involve non-synthetic/functionalization reactions that introduce or uncover a hydrophilic functional group?

A. Phase I
B. Phase II
C. Phase III
D. Phase IV

Answer: A

Explanation: Phase II are synthetic/conjugation reactions where the drug or metabolite is attached to endogenous water-soluble molecules.

Phase III is when drug metabolite is eliminated from the cell via transporters in the cell membrane

Note: Phases I, II, and III do not imply sequence

Which of the following is not an example of a Phase I reaction?

A. Oxidation via CYP450 and CAD
B. Hydrolysis via ester hydrolysis, amidase, and epoxide hydrolase
C. Glucuronidation via UGT
D. Reduction via CYP450 and Azo Reductase

Answer: C

Explanation: Glucuronidation is a Phase II reaction.

Demethylation via CYP450 is another example of a Phase I reaction

Which of the following is not an example of a Phase II Reaction?

A. Sulfonation via SULT
B. Glutathione Conjugation via Glutathione-S-Transferase
C. Acetylation via NAT
D. PGP mediated removal

Answer: D

Explanation: PGP is an example of a Phase III reaction. Other phase III reactions include MRP (Multi-drug Resistance Proteins) and Solute Carrier Transporters like OATP and OCT

True/False: Phase I reactions often introduce small groups while Phase II reactions introduce larger groups

Answer: True

Explanation: Look at slide 7 of the section 12 intro slides

True/False: If [drug] is high, nonlinear kinetics apply for metabolism

Answer: True

Explanation: Mechanisms for metabolism are saturated

True/False: We can get the fraction of drug metabolized by 1 - Fm

Answer: False

Explanation: 1 - Fe gets us Fm

Which of the following are sites of extrahepatic metabolism?

A. SI
B. Vascular smooth muscle
C. Skin
D. All of the above

Answer: D

Explanation: When Non-renal clearance is greater than 1500 mL/min, the drug is metabolized faster than the rate of hepatic blood flow, so some of the drug is metabolized outside the liver. Therefore, extrahepatic metabolism is present

True/False: The first pass effect reduces drug bioavailability

Answer: True, obviously

True/False: For oral drugs, a high ERh implies poor bioavailability due to extensive FPM

Answer: True

Explanation: This is true. An ER that is high implies high efficacy of elimination (> 0.7)

Which of the following does not affect hepatic clearance?

A. Blood flow
B. Intrinsic Clearance
C. Protein Binding
D. Literally dying
E. None of the above

Answer: E

Explanation: For more on blood flow, it can vary due to diet, physical activity, and drugs like beta blockers

Which of the following statements regarding reduced bioavailability is false?

A. Reduced bioavailability = F'
B. Q is needed to understand reduced bioavailability
C. F' represents the amount of drug absorbed before liver extraction
D. If F' = 0.35, then 35% of drug is systemically absorbed after liver extraction

Answer: C

Explanation: F' represents the amount of drug absorbed after liver extraction

Which of the following statements does not describe drugs with a high ER?

A. Rate of drug metabolism is almost as high as the blood flow perfusing the liver
B. Rate of drug metabolism is lowered
C. It is influenced by blood flow (flow dependent)
D. In a drug with a high ER, decreased cardiac output by beta blockers would decrease Q, thus increasing Cp

Answer: B

Explanation: This describes a drug with a low ER

Edit: I don't know what this even means, sorry

True/False: Drugs with low ER have a lower rate of drug metabolism, so they are metabolized independent of Q and are influenced by changes in enzyme function

Answer: True

Explanation: Enzyme induction and inhibition can affect metabolism of drugs with low ER

True/False: Intrinsic clearance (Clint) reflects the inherent activities of all enzymes involved in a drug's biotransformation

Answer: True

Explanation: It has a relationship to Clh via Q (The equation may or may not be on the equation sheet, I haven't checked). As you increase Intrinsic Clearance, your ER increases rapidly at first and then plateaus

True/False: For low ER drugs, Clh is not affected by Clint

Answer: False

Explanation: Intrinsic clearance represent biotransformation by all enzymes in the body. So, having a low ER means that clearance is not due to hepatic blood flow, so changes in Clint will affect hepatic clearance.

Vice Versa, if you have a drug with a high ER, changes in Clint will not alter Clh that much

Which of the following statements is false?

A. For high ER drugs, the major determinant of Clh is Q
B. For low ER drugs, the major determinant of Clh is Clint
C. For low ER drugs, the rate of liver drug metabolism is equal to Clh x Ca
D. For high ER drugs, there is marked variation in elimination t1/2 within a population due to genetic variability

Answer: D

Explanation: This is the case for low ER drugs. High ER drugs are already subjected to high rates of biotransformation

True/False: In general, drugs with low Intrinsic Clearance tend to have a high ER, and vice versa

Answer: False

Explanation: Drugs with low intrinsic clearance tend to have low ER, and vice versa

True/False: Protein bound drugs are not easily metabolized, meaning they have restrictive clearance

Answer: True

Explanation: Only the unbound drug fraction (fu) can be metabolized.

So, hepatic clearance is related to fu and intrinsic clearance of free drug (Cl'int) when protein binding is taken into account

Which of the following is false regarding Flow-limited drugs?

A. ER is high
B. There can be low or high % protein binding
C. There is no change in Clh when you decrease binding
D. If you decrease Q, Clh increases
E. None of the above

Answer: D

Explanation: As you decrease Q, Clh decreases for Flow-limited drugs

Q < Cl'int

Clh = Q

Which of the following is false regarding Capacity Limited, Binding Insensitive Drugs?

A. ER is low
B. % protein binding is > 75%
C. Decreased protein binding increases Clh, but this may or may not be significant
D. Decreased Q does not affect Clh

Answer: B

Explanation: % protein binding is < 75%

Q > Cl'int

Which of the following is false regarding Capacity Limited, Binding Sensitive Drugs

A. ER is high
B. % protein binding is > 90%
C. As you decrease binding, Clh increases
D. As you decrease Q, there is no effect on Clh

Answer: A

Explanation: ER is low.

Q > Cl'int

Which of the following statements regarding biliary excretion is false?

A. Bile is produced in hepatic cells and enters the gall bladder
B. Drugs with a MW > 500 are excreted exclusively in the bile
C. This is an active process, so it is saturable
D. Excretion in the bile depends on MW and polarity
E. If MW < 500, it is exclusively excreted in the urine

Answer: E

Explanation: From MW of 300-500, the drug is excreted in both the bile and urine. < 300 MW is exclusively excreted in the urine

We can increase polarity by conjugation in phase II metabolic reactions like glucuronidation

True/False: Some drugs that are metabolized via glucuronidation can be hydrolyzed back to their parent drug and is reabsorbed into the blood flow only to go back into the GIT via the bile

Answer: True

Explanation: Polar glucuronides are hydrolyzed back to less polar parent drugs. This process is known as enterohepatic circulation.

The enzyme that takes part in this process is beta-glucuronidase.

Evidence of enterohepatic circulation is seen in a secondary peak after administration in the time/concentration graph

True/False: Enterohepatic circulation is important to consider in multiple drug dosing as well as large single doses

Answer: True

Explanation: This may lead to drug accumulation to toxic levels

True/False: Unbound or free [Css] is the major determinant of pharmacologic response

Answer: True

True/False: If you have a low ER, Csstotal = R / Q

Answer: False

Explanation: This is the case for a drug with a high ER. For a low ER, Csstotal = R / (fu x Cl'int)

At high ER, Clh = Q

At low Er, Clh = fu x Cl'int

True/False: Most ADRs are due to SNPs

Answer: True

Which of the following statements regarding CYP2D6 is true?

A. 65 common drugs are metabolized by CYP2D6, including Fluoxetine, Codeine, and Tamoxifen
B. It is highly polymorphic with over 100 alleles
C. Patients can be classified on their metabolizer status (i.e., poor) depending on how efficient their CYP2D6 is
D. B and C
E. All of the above

Answer: E

True/False: In general, an extensive metabolizer taking a certain drug may experience more adverse effects than a poor metabolizer

Answer: False

Explanation: Assuming the drug is not a prodrug, poor metabolizers would remove the drug less well, leading to possible buildup and toxicity. Extensive metabolizers have greater metabolic capabilities, leading to possible failure of therapy

True/False: If a drug is a prodrug, a poor metabolizer taking the drug may experience a failure of therapy

Answer: True

Explanation: They are unable to metabolize the drug to its active form well, leading to a decreased drug response

Which of the following may we need to alter to account for genetic polymorphisms?

A. Dl
B. Dm
C. T (dosing interval)
D. All of the above

Answer: D

Explanation: Altering Dl allows us to reach Css quickly, while altering Dm allows us to keep Css within therapeutic range.

Altering T (dosing interval) allows us to maintain Css and reduce fluctuation and accumulation

True/False: Dm is used to calculate Cl

Answer: True

True/False: In an ultrarapid metabolizer, in the case of a normal drug, we can increase Dm or decrease tau to get therapeutic concentrations

Answer: True

Why may genotype not be correlated with phenotype?

A. Genetic influences on other genes involved in metabolism (i.e., P-gp)
B. Environmental factors
C. Age/Gender
D. Disease states
E. Drug interactions
F. All of the above

Answer: F

True/False: Pharmacodynamics is the relationship between the drug concentration at the site of action and the effects of the drug

Answer: True

Explanation: Drug concentration at the site of action is usually related to drug concentration in the blood. The higher the blood concentration, the more effect we usually see

Which of the following are affected by PK characteristics?

A. Onset of action
B. Duration of action
C. Intensity of drug effect
D. All of the above

Answer: D

Which of the following statements regarding PD models is false?

A. It is not possible to directly measure drug levels at the site of action
B. When rapid equilibrium exists between the plasma concentration and the drug concentration at the site of action, the drug concentration in the blood can be used in the modeling process
C. The PD model describes the relationship between the drug concentration at the site of action and the time it spends there
D. None of the above

Answer: C

Explanation: The PD model describes the relationship between the drug concentration at the site of action and the observed drug effect.

True/False: The slope (S) seen in the linear model reflects the duration of action of the drug

Answer: False

Explanation: The slope reflects the potency of the drug. A steeper slope means you need less drug to have an effect.

E = S x C

E = intensity of effect, C = drug concentration at the site of action

True/False: E0 is the effect in the absence of drug (the baseline effect)

Answer: True

Explanation: An example of baseline effect is a patient's blood pressure before administration of an anti-hypertensive agent

Which of the following PD models allows us to compare relative potencies, as they extend over a large range of drug concentrations?

A. Linear Model
B. Log-linear Model
C. A model airplane, idk
D. All of the above

Answer: B

Explanation: The log in the model allows for a wide range of concentrations to be displayed.

Which of the following statements regarding the Emax Model is false?

A. Emax is the maximum effect resulting from the drug, which represents its intrinsic activity
B. EC50 is the drug concentration when the effect is 50% of the max effect (this helps to measure duration of action)
C. From this model, baseline and maximum effects can be estimated
D. None of the above

Answer: B

Explanation: EC50 is a measure of potency, not a measure of duration of action

True/False: According to the Emax model, the effect of a drug increases as the concentration at the site of action increases until it reaches a plateau at very low concentrations

Answer: False

Explanation: This plateau is reached at very high concentrations

True/False: The Sigmoid Emax model modifies the Emax model by adding N to the equation, which is related to the number of drug molecules bound to the receptor

Answer: True

Explanation: As n increases, the initial slope of the graph gets steeper and plateaus earlier.

True/False: A small n value indicates allosteric or cooperative effects of the drug at the effector site

Answer: False

Explanation: a large n (n = 20) indicates allosteric effects. A high n means the drug may start binding to other sites.

True/False: In a one-compartment model, the expected drug effect at a given plasma [drug] can be predicted at a certain time

Answer: True

True/False: If your drug acts in a peripheral compartment, the drug effect can be estimated by concentration of the drug in the central compartment

Answer: False

Explanation: Drug effect runs parallel to the [drug] in the peripheral compartment.

Why might we see a lag in drug effect after drug concentrations have distributed?

A. The drug concentration-effect relationship changes with time (such as in the case with prodrugs, I guess)
B. The drug may produce its effect by an indirect mechanism, such as the case with affecting the coagulation cascade
C. The drug may result in a hysteresis loop
D. All of the above

Answer: D

Which of the following statements regarding a hysteresis loop is false?

A. They use arrows to represent a series observations
B. At a given plasma [drug], the drug effect will be different depending on whether the [drug] is increasing or decreasing
C. It measures a concentration-dependent response
D. None of the above

Answer: C

Explanation: They hysteresis loop helps us understand the time-dependent pharmacological response

True/False: In the case of lorazepam, drug concentrations at the site of action is not in rapid equilibrium, so a lag time exists due to time required to penetrate CNS tissues (slow distribution). So, plasma [lorazepam] does not correlate with drug effect observed at time of sampling

Answer: True

Explanation: This is so confusing, who let this happen

True/False: In the case of drug tolerance, we often see counter-clockwise hysteresis

Answer: False

Explanation: We often see clockwise hysteresis in drugs that produce tolerance (high effect initially, low effect later).

You see a decrease in effect with time event though drug concentrations are increasing, usually from a decrease in number of receptors

Which of the following are assumptions we make about the effect compartment?

A. It is a hypothetical compartment that links PK and PD models
B. Drug transfer from plasma to effect comp does not affect PK of the drug
C. Drug transfer is first order
D. Drug effect is determined by [drug] in the effect compartment
E. All of the above

Answer: E

Explanation: Effect compartments are used when there is a time delay between plasma [drug] and effect (such as in the case of a hysteresis loop)

True/False: In the case of an effect compartment, the transfer rate constant Ke0 determines the pharmacological response

Answer: True

Explanation: The PD response can now be plotted versus Ce, which accounts for lag time, fitting the sigmoid Emax model

This allows us to have a better understanding of time course of the drug response

True'False: In a PK model, increasing the dose prolongs the duration of effect, but the duration of effect is not proportional to the administered dose

Answer: True

Explanation: Doubling the dose will prolong its effect, but this will not double the duration.