Pathophysiology and Drug Action Exam 3

Question 1

What is ADME?

Answer 1

-how the drug enters the body (absorption)
-where it goes once it enters (distribution)
-how it is broken down within the body (metabolism)
-how it is removed from the body (excretion)

Question 2

What are the three primary means to quantify drug effect?

Answer 2

Onset: how quickly the drug exhibits its pharmacologic effect
Duration: how long it exhibits its effect
Intensity: magnitude of the pharmacologic effect

Question 3

What are some barriers associated with ADME?

Answer 3

-membranes that limit the movement of drug into certain tissues
-enzymes within membranes that metabolize the parent drug
! can reduce amount of drug that reaches receptor as well as speed it reaches site

Question 4

What will a reduction in the extent of absorption result in?

Answer 4

-reduces peak drug concentration and time the drug remains above the MEC
-reduce intensity and duration

Question 5

What will a reduction in speed of entry into systemic circulation result in?

Answer 5

-effects onset

Question 6

What happens if a parent drug is active and a metabolite is inactive and they get co-administrated?

Answer 6

co-administration of the inhibitor of the metabolism of the parent drug will prolong the pharmacologic effect

Question 7

What happens if a parent drug is inactive and a metabolite is active and they get co-administered?

Answer 7

-giving an inhibitor of the metabolism of the parent drug will decrease the pharmacologic effect

Question 8

What are the factors that determine movement of a drug across membranes?

Answer 8

1. Characteristics of the membrane
2. Mechanisms of passage across membrane
3. Dwell time of drug-membrane interface
4. Physiochemical characteristics of the drug
5. pH of the microenvironment
6. Surface area of absorptive surface

Question 9

What is the site in the GI tract that involves the most absorption?

Answer 9

-Small Intestine
is covered by folds of Kerckring (villi and microvilli) increases surface area

Question 10

What are the mechanisms by which Drugs cross Biological Membranes?

Answer 10

-Paracellular, Transcellular (passive), Facilitated Diffusion (carrier-mediated), Active transport (carrier-mediated)

Question 11

What are the effects of carrier-mediated transport?

Answer 11

facilitated diffusion and active transport are saturable and susceptible to competitive inhibition;
facilitated diffusion only moves molecules with a concentration gradient; passive
active transport requires energy (ATP); can go against the concentration gradient

Question 12

How do efflux transporters affect the absorption of a drug in the small intestine?

Answer 12

-Transport proteins that facilitate movement of solutes out of the cell are efflux transporters
1. Limited drug absorption
2. Enhanced drug elimination
3. Limited distribution

Question 13

How do nanoparticles cross biological membranes?

Answer 13

-Endocytosis
-usually for large molecules and nanoparticle drug delivery

Question 14

How is transcellular permeability increased?

Answer 14

1. Removing charged (ionized) groups
2. Increasing lipophilicity
3. Reducing size
   consequence: more lipoplhilic(cross membranes)—> less soluble(less absorbed)—–>poor bioavailability

Question 15

What is the effect of drug distribution on the concentration versus time curve?

Answer 15

-distributes into perfuse tissues first; then concentration increases in other tissues
-after equilibrium is reached; tissue and plasma are parallel in decline even though concentrations are not the same in each tissues the decline is

Question 16

what are the differences between perfusion rate limited and permeability rate limited distribution of drug tissues?

Answer 16

-Permeability rate limited will show slower perfusion rate because the solute can only get across the membrane so fast
-Perfusion rate limited is going across the membrane NOT going to the organ

Question 17

Differentiate between transvascular movement and via convection versus diffusion

Answer 17

-Convection is driven by pressure; used by large molecules
-Diffusion is driven by concentration gradient from high concentration to low concentration

Question 18

How does drug “trapping” occur?

Answer 18

-uses the pH partition phenomenon
-ionizes certain drugs so it can excreted in the urine
-results in differences in drug concentration compared to blood

Question 19

How does plasma protein binding effect distribution and pharmacologic effect?

Answer 19

-free drug is the pharmacologically active species and therefore when drug is bound it is inactive and can change distribution of a drug

Question 20

What are 4 mechanisms that allows drug access to the CNS?

Answer 20

-appropriate physiochemical properties
-utilize an existing transporter
-disruption of the blood brain barrier (osmotic load chased by drug; risk of toxicity)
-direct administration into the CNS (cerebrospinal fluid)

Question 21

What type of drug molecule is best to used with a pregnant woman?

Answer 21

-highly polar charged drugs
-can’t cross the placenta

Question 22

What are the main routes drugs are excreted from the body?

Answer 22

-Renal and biliary (hepatic)
-other routes: salivary, pulmonary, mammary

Question 23

What are the main processes and location involved in renal excretion?

Answer 23

-filtration -Glomerulus
-active tubular secretion -proximal tubule
-tubular reabsorption -proximal tubule
-biotransformation -proximal tubule

Question 24

How does physiochemical properties of a drug influence its filtration?

Answer 24

-molecular size
-protein binding

Question 25

What is the relationship between molecular weight and renal clearance?

Answer 25

if molecular size is too big (MW<500) it will not get filtered through renal clearance
-smaller the molecule, the more the renal clearance will occur

Question 26

What is the relationship between dose and urinary excretion rate for a drug that only goes through filtration vs one eliminated through renal secretion?

Answer 26

-renal clearance increases as creatinine clearance increases
-drugs that go through renal secretion are susceptible to competitive binding (exhibits saturation at high concentration) and can be stereoselective

Question 27

What is the relationship between molecular weight and percent of drug excreted in the bile?

Answer 27

-the larger the molecular weight (~500-600 optimal) larger the percent excreted in the bile; conjugated drugs also excreted in bile
-less than 300-400 MW will be reabsorbed by kidneys and not excreted in the bile
-also whether polar or not (polar gets eliminated in bile)

Question 28

What is the impact of enterohepatic recirculation regarding drug half-life in the body?

Answer 28

-increases half life
-conjugated drugs can be hydrolyzed in GI tract and reabsorbed
-reduces elimination of xenobiotics

Question 29

what are the CYP3A4 substrates, inhibitors, and inducers?

Answer 29

substrates: midazolam, indinavir
inhibitors: ritonavir, ketoconazole
inducers: rifampin, St. John’s Wort

Question 30

What are CYP2D6 substrates, inhibitors, and inducers?

Answer 30

substrates: fluoxetine, codeine
inhibitors: fluoxetine, quinidine
inducers: no clinical relevance

Question 31

What are CYP2C9 substrates, inhibitors, and inducers?

Answer 31

substrates: S-warfarin, ibuprofen
inhibitors: fluconazole, amiodarone
inducers: rifampin, secobarbital

Question 32

What is the primary organ involved in drug metabolism?

Answer 32

-Liver

Question 33

What are some differences between Phase I and Phase II metabolism?

Answer 33

-Phase I involves biotransformation (chemical modification; oxidation) which introduces new functional groups for Phase II reactions
-Phase II involves conjugation of a polar group with drug

Question 34

When given a specific CYP450, name the family, subfamily, individual gene, and allelic variant component

Answer 34

CYP(2-family)(D-subfamily)(6-Individual gene) *1A(allele)

Question 35

What are the differences between the mechanism of reversible and irreversible CYP450 inhibition?

Answer 35

-reversible CYP450 inhibition compete with substrates for occupancy of active site of same CYP enzyme
-irreversible CYP450 inhibition is mechanism-based (suicide inhibition); most potent and longest-acting type of inhibitor

Question 36

Why does an enzyme inducer increase the metabolism of drugs metabolized by different CYP450’s?

Answer 36

-the drugs bind to/induce transcription factor proteins which induce transcription of CYP genes which in turn increases CYP450’s which increases overall metabolism
-lots of cross-talk

Question 37

What are the Phase II metabolic processes?

Answer 37

UGT (glucuronidation) involved in conjugation of many functional groups
SULT (sulfotransferases) for steroid hormones, catecholamine neurotransmitters, phenolic drugs
NAT (N-acetyltranferases)

Question 38

Why is genetic variation not the most important factor in determining variation in drug concentration and clinical response?

Answer 38

-there is a huge source of variation in responses because there are so many factors that affect metabolism and differences in each person in all these factors