Pharmacology E1

Question 1

Controlled substances scheduling system

Answer 1

Schedule I – high potential for abuse; no accepted medical use (eg, heroin)

Schedule II – high potential for abuse; currently accepted medical use (eg, morphine)

Schedule III-V
Lesser potential for abuse

Schedule VI
All other prescription drugs

Question 2

Pregnancy risk categories

Answer 2

Category A – studies fail to demonstrate risk to fetus in first trimester, no evidence of risk in later trimesters

(category B/C/D/X higher risk)

Question 3

EC50

Answer 3

The molar concentration of an agonist that produces 50% of the maximal possible effect of that agonist, can be stimulatory or inhibitory

Question 4

ED50

Answer 4

Dose of drug that produces, on average, a specific all-or-none response in 50% of a test population

if the response is graded –> dose that produces 50% of the maximal response to that drug

Question 5

Antagonist

Answer 5

drug that reduces the action of an agonist, often acting by the same receptor

Question 6

Competitive antagonism

Answer 6

Result: apparent dec in affinity, no change in maximal response

• binding of agonist and antagonist is mutually exclusive
• usually surmountable (with inc [agonist])
• shift to RIGHT

Question 7

Noncompetitive antagonism

Answer 7

insurmountable

Antagonist could inactivate receptors, leading to dec in maximal response, but no change in affinity of the remaining receptors

Question 8

LD50

Answer 8

dose of the drug that produces death in 50% of a population of test animals

Question 9

Therapeutic Index

Answer 9

ratio of LD50 to ED50 (or LC50:EC50) –> relative indication of safety. Want a higher #

*need to avoid overlap between high end of therapeutic effect and low end of toxic effect, bc pts may req larger, potentially toxic doses
(want a wide window)

Question 10

Therapeutic window

Answer 10

range of drug concentrations in blood which produce a therapeutic response without unacceptable toxicity

Question 11

Efficacy

Answer 11

Efficacy = Fraction of Emax attained

partial agonist does not attain Emax

Question 12

pKa of a drug

Answer 12

pH w/ [ionized form]=[non-ionized form]

acidic drug in pH < pKa –> mostly non-ionized (protonated)
basic drug in pH < pKa –> mostly ionized (protonated)

*uncharged forms readily pass thru membranes

Question 13

An acidic drug with pKa of 5 will be in what form in blood, stomach?

Answer 13

blood: mostly ionized, non-protonated
stomach: mostly non-ionized, protonated

Question 14

A basic drug with pKa of 5 will be in what form in blood, stomach?

Answer 14

blood: mostly non-ionized (non-protonated)
stomach: mostly ionized (protonated)

Question 15

Kidney excretion of drugs

Answer 15

ionized drugs excreted, non-ionized reabsorbed

if acidify urine –> basic drugs excreted
if alkalinize urine –> acidic drugs excreted

Question 16

Concerns for breast milk

Answer 16

When mother is taking basic drugs (narcotics), bc milk is more acidic, they will be concentrated in the milk

Question 17

Volume of distribution

Answer 17

Vd=dose/Cp (units of vol)

relates amount of drug in body to [drug]plasma

not a real volume
related to lipid solubility but does not tell you where drug is

Question 18

Loading dose

Answer 18

Dl=Vd * desired Cp

if any other routes, oral etc, include bioavailability
Dl=(Vd * Cp)/F

Question 19

Clearance

Answer 19

Cl= dose rate/Cp (steady state)

measure of vol of plasma cleared of drug content per unit time

units of vol/time

Also:
Cl = dose / AUC

Cl = Vd x k

Cl = Q x E

Question 20

weak acids, which form is nonionized/ionized?

Answer 20

protonated, non-ionized

non-protonated, ionized

Question 21

weak bases, which form is nonionized/ionized?

Answer 21

non-protonated, nonionized

protonated, ionized

Question 22

Sites of drug metabolism

Answer 22

*Liver
Intestine
Lungs
Kidneys
Placenta
Plasma

Question 23

first-pass metabolism

Answer 23

process by which some orally administered drugs are metabolized by the GI/liver such that only a fraction of what is administered reaches the systemic circulation

also called “pre-systemic extraction”

Question 24

Microsomal enzymes

Answer 24

• Cytochrome P450 (CYPs)
• UDP Glucuronosyltranferases (UGTs)

others:
NADPH-CYP reductase
Glutathione S-tranferases
Epoxide hydrolases
Flavin-containing monooxygenases (FMOs)
Carboxyl esterases
Aldehyde dehydrogenases

Question 25

Phase I Drug Metabolism

Answer 25

Phase I (more active change) - CYP 450 (oxidation)* - Alcohol & aldehyde oxidation - Azo & nitro reduction - Hydrolysis

Question 26

Phase II Drug Metabolism

Answer 26

``` Phase II (more passive change) Glucuronidation* Acetylation Sulfate conjugation Methylation ```

Question 27

Cytochrome P450 enzymes - most important quantitatively?

Answer 27

CYP3A4/5 - written as CYP3A (more than 50% of currently marketed drugs) In both liver and intestinal mucosa

Question 28

Most common conjugation rxn

Answer 28

Glucuronidation Multiple UDP-glucuronosyltransferases UGT1A1 & UGT2B7 most studied Substrates: Lorazepam, Morphine, Zidovudine (AZT)

Question 29

Prodrug

Answer 29

If the “drug” is inactive and the “metabolite” is active exp. plavix, codeine

Question 30

Acetaminophen and hepatotoxicity

Answer 30

Normally involves direct conversion to no n-toxic glucuronide metabolites Small amount of clearance mediated by CYP450 enzymes --> yields toxic NAPQI (usually conjugated to glutathione, but only so much) --> hepatotoxicity

Question 31

Risk fx for acetaminophen toxicity

Answer 31

Anything that inc bioactivation (inc specific CYP enzyme activity) Anything that impairs detoxification Anything that depletes glutathione levels

Question 32

Sources in variability in drug metabolizing

Answer 32

*Genetics (polymorphisms such as CYP2D6, CYP2C19, acetylation, others) *Other drugs Disease states Habits (smoking, exercise) Diet Environment Age (+/-) Gender (+/-)

Question 33

Most important transporter, functions to protect body from unfavorable foreign substances

Answer 33

P-glycoprotein (P-gp), known as Multidrug resistance-associated protein (MRP)

Question 34

Determinants of bioavailability

Answer 34

Cmax: peak-plasma concentration Tmax: Time of peak concentration AUC: area under the plasma concentration curve (systemic exposure) measure of rate and extent of absorption

Question 35

First order behavior

Answer 35

Rate of elimination --> proportional to Cp Clearance --> independent of Cp, constant - A constant FRACTION of drug removal per unit time. *most drugs exhibit this

Question 36

Zero order behavior

Answer 36

Rate of elimination --> independent of Cp, constant Clearance --> dependent on Cp - A constant AMOUNT of drug removal per unit time. *usu occurs when elimination process is saturated

Question 37

Inhibitors

Answer 37

dec enzyme activity leading to a dec in metabolite prod plasma levels of parent drug --> inc clinical effect --> enhanced *opp for prodrug

Question 38

Inducers

Answer 38

inc enzyme activity leading to increase in metabolite being made plasma levels of parent drug --> dec clinical effect --> diminished *opp for prodrug

Question 39

Important routes of drug administration

Answer 39

``` Oral (P.O.) Parenteral -subcutaneous (SC) -intramuscular (IM) -intravenous (IV) ```

Question 40

Bioavailability

Answer 40

Fraction of drug absorbed systemically after extravascular vs. intravascular admin (F) F=AUC(oral)/AUC(IV) >0.90 --> Better 0.02 --> crappy

Question 41

Reasons for low bioavailability

Answer 41

``` Poor absorption Pre-systemic extraction (first-pass metabolism) -hepatic -enteric (CYP3A) Efflux transport (P-glycoprotein) ```

Question 42

Two most common pharmacokinetic drug interactions

Answer 42

Absorption (binding/chelation vs pH related) | Metabolism (induction vs inhibition)

Question 43

Aminoglycoside Kinetics (eg, gentamicin, tobramycin, amikacin)

Answer 43

Not absorbed orally Poor lipid solubility Little protein binding Vd usually around 0.3 L/kg (low) Metabolism - none Excretion - primarily renal

Question 44

Genetic polymorphisms

Answer 44

SNPs *frequent, don't prod change usually | Indels *infrequent but higher likelihood of having functional effect

Question 45

CYP450 polymorphisms

Answer 45

``` select alleles (CYP450 2C19*3) - European and East Asian population --> poor metabolizers Common substrates: omeprazole, plavix *prodrug, so will be more INACTIVE with this drug, bc cant convert it into active form via CPY enzymes ```

Question 46

Whole gene polymorphisms

Answer 46

CYP450 2D6 - african Americans, europeans, Ethiopians*** --> ultraRAPID metabolizers Exp: antidepressants, antipsychotics. Codeine, tamoxifen --> both PRODRUGS, so this population will form active form FASTER --> more likely to have toxicity ^greater ant codeine --> morphine

Question 47

Consequences of being poor metabolizer

Answer 47

``` Reduced first pass effect -inc oral bioavailability (inc frac of orally admin drug that reaches systemic circulation) -inc plasma levels Reduced metabolic clearance -inc half life -inc accumulation w/ repeated doses Alternate pathway metabolism Failure to activate prodrugs Not affected by inhibitors ```

Question 48

Genetic changes that lead to impaired warfarin metabolism

Answer 48

CYP2C9 (pharmacokinetic) or VKORC1 (pharmacodynamic, responsible for clotting factor activation) alterations 60% of variability still explained by other factors (age, weight, comorbidities, etc)

Question 49

If HLA genetic change involved... greater risk for

Answer 49

alergic rxn would req pharmacogenetic testing

Question 50

Barriers to pharmacogenetics testing in clinical practice

Answer 50

Resistance to abandon “trial & error” approach Concern about genetic discrimination Unfamiliarity with principles of genetics Lack of outcomes data Affordability

Question 51

If both the infusion rate and the concentration at steady state are known, what can be determined?

Answer 51

Clearance