Exam 3 Flashcards by Renee W

What does ADME stand for?

Absorption, Distribution, Metabolism, and Excretion

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What are the three primary means to quantify drug effect?

Onset, duration and intensity

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What goes on 1, 2, and 3?

1: Intensity
2: Duration
3. Onset

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What happens onset, intensity and duration on the red line in comparison to the black?

Onset: same, intensity: decreases, duration: increases

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Two reasons why less than 100% of a dose may reach the site of action

Degradation and excretion

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The study of the absorption, distribution, biotransformation, and elimination of xenobiotics

pharmacokinetics

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The study of the molecular, biochemical, and physiological effects of xenobiotics and their mechanisms of actions

pharmacodynamics

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The fate of a drug after it has entered the systemic circulation

drug disposition

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What three aspects make up pharmacotherapeutics?

pathophysiology, pharmacodynamics, and pharmacokinetics

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What was the greatest reason why drugs failed in Phase I of clinical trials in 1991? What was the %? What changed to lower the percentage (and what’s the %s value)?

Biggest reason: pharmacokinetics/bioavailability (40%)
Development of improved preclinical ADME greatly reduced drug attrition due to poor PK/bioavailability (<10%)

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What route of administration has the most rapid onset? Slowest?

Fastest: IV slowest: smoked

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What are the four routes of administration?

ingestion, inhalation, dermal, and parenteral

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A reduction in the extent of absorption will impact which of the three measures of pharmacologic effect: onset, intensity, and/or duration?

Intensity

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A reduction in the speed of entry into the systemic circulation will impact which of the three measures of pharmacologic effect: onset, intensity, and/or duration?

Onset

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Barriers and blood flow can impact both the speed and extent of ________ of a drug in the body

distribution

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Of the four consequences of metabolism, what process is used for active to inactive metabolites?

phenobarbital -hydroxylation-> Hydroxyphenobarbital

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Of the four consequences of metabolism, what process is used for active to active metabolites

Procainamide -acetylation-> N-acetylprocainamide

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Of the four consequences of metabolism, what process is used for inactive to active metabolites

Codeine -demethylation-> morphine

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Of the four consequences of metabolism, what process is used for active to reactive metabolites

Acetaminophen -> reactive metabolite

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A ______ in the extent of absorption will reduce the peak drug conc. and the time the drug conc. remains above the minimally effective conc.

reduction

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A reduction in the speed of entry into the systemic circulation will (inc/dec) the time it takes for the drug conc. to reach the minimally effective conc. Which part of the curve will be most impacted?

increase; the onset

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What barrier can significantly reduce the amount of drug that enters the site of action?

tissue

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The graph below shows the conc vs time curve for two formulations of a bupropion. Compared to “Budeprion XL” (green), the maximal intensity of the pharmacologic effect for “Wellbutrin XL (red)” would be expected to occur:
a. later
b. sooner
c. at the same time

a. later

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What percent of drug currently fail in clinical trials due to problems with the ADME of the compounds?
A. ~40%
B. <10%
C. 25%

B. <10%

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Which route of admin. would be expected to produce the most rapid onset of pharmacologic effect? a. oral b. dermal c. subcutaneous d. intravenous e. intramuscular

d. intravenous

Morphine is a metabolite of codeine and this metabolite is responsible for the analgesic effect when codeine is admind. In a patent who has a genetic defect such that they cannot metabolize codeine, the magnitude of pain relief would be expected to be (incr/decr/same) compared to normal pateints?

decreased

Which route of admin. avoids the need to cross a biological membrane in order to reach the systemic circulation?

intravenous

Which route of admin. avoids the need to cross a biological membrane in order to reach the CNS?

None

What impact would a drug that speeds up stomach emptying (metoclopramide) have on the time to peak conc for acetaminophen?

The peak drug conc would be higher

In Fick's equation, if the diffusion rate increases, what happens to the concentration?

Increases directly

For a drug which undergoes passive diffusion, the rate of transport across the membrane should (incr/decr/same) as the concentration increases

increase

What site in the GI tract is where most drug absorption occurs? Why?

Small intestine: covered in folds of Kercking with villi containing microvilli. This increases the surface area and transit time (~3-5hrs)

The passive movement of drug through lipid membranes

transcellular diffusion

The passive movement of drugs between cells via tight junctions.

paracellular diffusion

A carrier-mediated process that involves a transport protein which moves drug with a conc. gradient

facilitated diffusion

A carrier-mediated process that requires energy.

active transport

What types of transport are passive? Carrier-mediated?

Passive: transcellular and paracellular Carrier-mediated: facilitated and active

Which transports are driven or move with a concentration gradient? A. Transcellular B. Facilitated C. Paracellular D. Active Transport

trans and para driven and facilitated moved

In a base solution, which pKa(><=)pH is favorable? Acid?

Base: pKapH favorable

T or F: Gastrointestinal transit time does NOT influence the extent and rate of drug absorption

False

What type of diffusion in saturable and subject to competitive drug-drug interactions?

passive

Transporter that removes solute (drug) out of the cell, reducing the amount of drug that accumulates in certain tissues, such as the brain

Efflux transporters

Slowing gastric emptying would be expected to have what effect on the absorption of a drug absorbed by passive diffusion? a. it will take longer to achieve the peak conc. b. the peak conc. will occur sooner c. slowing gastric emptying will have no effect on the timing of the peak conc. of the drug

a. it will take longer to achieve the peak conc.

Which of the following mechanisms moves drug down a conc gradient? a. Paracellular diffusion b. Transcellular diffusion c. Facilitated diffusion d. active transport e a&b f a, b, & c g. All of the above

f. a, b, and c

Co-admin of an inhibitor of the efflux protein p-glycoprotein (pgp) would be expected to have what effect on the oral absorption of a drug that is a substrate for pgp? a. the inhibitor of pgp will increase the amt of drug absorbed b. the inhibitor of pgp will decrease the amt of drug absorbed c. the inhibitor of pgp will not change the amt of drug absorbed

a. the inhibitor of pgp will increase the amt of drug absorbed

Which of the following modifications would be not expected to increase the transcellular permeability of a drug molecule? a. Removing ionized groups b. Decreasing lipophilicity c. Reducing molecular size

b. Decreasing lipophilicity

What type of cell movement is frequently used for nanoparticle drug delivery?

endocytosis

A process by which a cell engulfs and internalizes a particle

endocytosis

Describe the effect of drug distribution on the concentration vs time curve: When is the highest dose achieved? Profusion?

Highest dose is achieved right after drug is administered. Highly profuse tissue will distribute drug more rapidly.

Differentiate between perfusion rate limited and permeability rate limited distribution of drug into tissues

Perfusion rate limited: little membrane barrier causing more rapid movement of molecules from blood to body tissues Permeability rate limited: greater membrane barrier causing lower movement of molecules from blood to body tissues

The movement of drug molecules across vascular endothelial cells and into tissue interstitial space

transvascular transport

A transvascular transport process that is driven by pressure

convection

A transvascular trasnport process that is driven by a concentration gradient

diffusion

Will perfusion rate limited or permeability rate limited show slower tissue distribution?

Permeability

What method of transvascular transport is likely to be important for monoclonal antibodies?

Convection

Describe how differences in tissue pH may result in the trapping of ionizable drugs

When going from a higher pH to lower pH, the drug may be uncharged in the higher pH allowing it to be transported through the membrane then become charged in the lower pH, "trapping" it from crossing the membrane and allowing excretion

Describe how plasma protein binding effects distribution and pharmacologic effect

Drugs bound to plasma proteins limit distribution in tissues since only free drug can cross endothelial membrane

4 ways drug may gain access to the CNS

(Appropriate DDT) *appropriate physiochemical properties *Disruption of the blood brain barrier *Direct admin into CNS (most common: spinal tap) *Utilize an existing transporter

How to choose the best meds for a pregnant woman

Free drug will pass through fetal liver, so we want a large molecule

The conc of drug within a tissue due to pH difference that lead to ionization of the drug in the tissue environment

drug trapping

The initial movement of drug from highly perfused tissues to poorly perfused tissues

redistribution

What organ is called a "privileged site"? why?

Brain- it excludes many compounds from entering the CNS

What efflux transporter is used in the CNS to prevent drugs from accumulating in the brain?

p-glycoprotein (pgp or MDR1)

(Polar/Non-Polar) drugs do NOT usually cross the placenta

Polar- its the best choice for prego women

T or F: A drug that is only distributed into vascular space will exhibit a monoexponential blood conc vs time curve after intravenous admin.

True

Which of the following drugs is most likely to undergo transvascular transport via convection? a. asprin (MW 180 g/mole) b. cimetidine (MW 252 g/mole) c. Vancomycin (MW 143 g/mole) d. Idarucizumab (MW 48k Daltons) e. a, b, c f. none of the above

d. Idarucizumab (MW 48k Daltons)

A decrease in the plasma protein binding of a drug would be expected to have what effect on the distribution of drug into tissue? A. a decrease in protein binding will increase the amount of drug in tissue B. A. a decrease in protein binding will decrease the amount of drug in tissue A. a decrease in protein binding will not change the amount of drug in tissue

A. a decrease in protein binding will increase the amount of drug in tissue

A change in the structure of a drug molecule such that it is no longer transported by pgp (MDR1) would be expected to have what effect on the CNS conc. of drug compared to the original drug? A The new drug would have a lower conc. in the CNS B The new drug would have a higher conc. in the CNS C. A The new drug would have the same conc. in the CNS

B The new drug would have a higher conc. in the CNS

The primary route drugs are excreted from the body

renal (kidney) and hepatic

Identify the key process and anatomical location involved in renal excretion

Filtration: beginning (afferent) Secretion: Proximal convoluted tubule (PCT) Absorption: Loop of Henle Biotransformation

What is the relationship in glomerular filtration?

What is the molecular size limit for glomerular filtration?

MW<5000

Creatinine vs clearance relationship for a drug eliminated by filtration

Elimination of which of the following drug molecular weight would be unaffected by renal disease? A. ~15,000 B. 500 C. 10

A. 15,000

Drugs that undergo ATC are... A. susceptible to competitive interaction B. exhibit stereoselective renal excretion C. Unsaturable D. Only A and B E. All of the above

D. (C should be saturable)

The active transport of drug from blood into the renal tubule, occurring primarily in the proximal tubule

Active tubular secretion (ATS)

The movement of solute from inside the renal tubule back into the blood. Passive and driven by high conc. that occurs as a result of the large fraction of filtrate that is reabsorbed.

Tubular reabsorption

The reabsorption of drug from the small intestine after drug has been excreted through the bile into the intestine

enterohepatic recirculation

The process by which food stimulates release of bile, and drug contained therein, into the small intestine, followed by reabsorption of the drug.

dose dumping

What is glomerular filtration largely influenced by?

Molecular size and plasma protein binding

T of F: Most tubular reabsorption is driven by carrier-mediated diffusion

F: concentration gradient (passive)

When (this type of reabsorption) occurs, the process is saturable.

carrier-mediated tubular reabsorption

What are the two processes of hepatic elimination?

metabolism (biotransformation) and biliary excretion

First or second pass effect: Blood draining the stomach and small intestine flowing into the portal vein, all absorbed drug passing through the liver before entering the rest of the body

First

T or F: pgp secretes drug from the hepatocyte into bile

What are the primary factors determining biliary secretion?

Molecular weight and polarity

(Small/Large) polar molecules are mostly eliminated in the bile

Large

Which of the following renal excretory processes for drugs is most likely subject to competitive drug-drug interactions? a. filtration b. tubular secretion c. tubular reabsorption d. b and c e all of the above

In examining the renal elimination of a series of chemically related compounds, as molecular weight increases the extent of filtration will (increase/decrease/not have an influence)

decrease

If enterohepatic recirculation (EHR) increases, the half-life of a drug will (Increase/decrease/no effect)

increase

For a drug that is eliminated solely by glomerular filtration, a decrease in plasma protein binding will result in an (incr/decr) in the renal elimination of the drug

increase

Which of the following vitamins undergo bioactivation in the kidney? a. Vit A b. Vit B c. Vit C d. Vit D e. Vit E

d. Vit D

Half-life (t 1/2) is influenced by _______

metabolism

What is the first organ exposed to compounds absorbed in the gut?

Liver

Which phase (I or II) using chemical modification (biotransformation) including oxidation, hydroxylation, etc. to introduce new functional group or expose group

Phase I

Which phase (I or II) conjugated the polar group with drug

Phase II

Phase I reactions typically occur by (oxidation/reduction) and are catalyzed by (cypP450/NADPH/O2) utilizing (cypP450/NADPH/O2) and (cypP450/NADPH/O2)

Phase I reactions typically occur by oxidation and are catalyzed by cypP450 utilizing NADPH and O2

CYP2D6*1A Identify the allele, subfamily, family and individual gene

CYP2(Family)D(subfamily)6(individual gene)*1A(allele)

The active site of CYP contains an ____-_____ cofactor

iron-heme

Factors that determine binding strength in reversible inhibition

coordination, hydrophobic, and specific contacts