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Emma II > Pharmacology E1 > Flashcards

Pharmacology E1 Flashcards

1
Q

Controlled substances scheduling system

A

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

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2
Q

Pregnancy risk categories

A

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)

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3
Q

EC50

A

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

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4
Q

ED50

A

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

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5
Q

Antagonist

A

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

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6
Q

Competitive antagonism

A

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
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7
Q

Noncompetitive antagonism

A

insurmountable

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

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8
Q

LD50

A

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

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9
Q

Therapeutic Index

A

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)

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10
Q

Therapeutic window

A

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

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11
Q

Efficacy

A

Efficacy = Fraction of Emax attained

partial agonist does not attain Emax

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12
Q

pKa of a drug

A

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

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13
Q

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

A

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

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14
Q

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

A

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

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15
Q

Kidney excretion of drugs

A

ionized drugs excreted, non-ionized reabsorbed

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

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16
Q

Concerns for breast milk

A

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

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17
Q

Volume of distribution

A

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

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18
Q

Loading dose

A

Dl=Vd * desired Cp

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

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19
Q

Clearance

A

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

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20
Q

weak acids, which form is nonionized/ionized?

A

protonated, non-ionized

non-protonated, ionized

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21
Q

weak bases, which form is nonionized/ionized?

A

non-protonated, nonionized

protonated, ionized

22
Q

Sites of drug metabolism

A 
*Liver
Intestine
Lungs
Kidneys
Placenta
Plasma
23
Q

first-pass metabolism

A

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”

24
Q

Microsomal enzymes

A
  • Cytochrome P450 (CYPs)
  • UDP Glucuronosyltranferases (UGTs)
others:
NADPH-CYP reductase
Glutathione S-tranferases
Epoxide hydrolases
Flavin-containing monooxygenases (FMOs)
Carboxyl esterases
Aldehyde dehydrogenases
25
Q

Phase I Drug Metabolism

A

Phase I (more active change)

  • CYP 450 (oxidation)*
  • Alcohol & aldehyde oxidation
  • Azo & nitro reduction
  • Hydrolysis
26
Q

Phase II Drug Metabolism

A 
Phase II (more passive change)
Glucuronidation*
Acetylation
Sulfate conjugation
Methylation
27
Q

Cytochrome P450 enzymes - most important quantitatively?

A

CYP3A4/5 - written as CYP3A (more than 50% of currently marketed drugs)

In both liver and intestinal mucosa

28
Q

Most common conjugation rxn

A

Glucuronidation

Multiple UDP-glucuronosyltransferases
UGT1A1 & UGT2B7 most studied

Substrates: Lorazepam, Morphine, Zidovudine (AZT)

29
Q

Prodrug

A

If the “drug” is inactive and the “metabolite” is active

exp. plavix, codeine

30
Q

Acetaminophen and hepatotoxicity

A

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

31
Q

Risk fx for acetaminophen toxicity

A

Anything that inc bioactivation (inc specific CYP enzyme activity)

Anything that impairs detoxification

Anything that depletes glutathione levels

32
Q

Sources in variability in drug metabolizing

A

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

33
Q

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

A

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

34
Q

Determinants of bioavailability

A

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

35
Q

First order behavior

A

Rate of elimination –> proportional to Cp
Clearance –> independent of Cp, constant
- A constant FRACTION of drug removal per unit time.

*most drugs exhibit this

36
Q

Zero order behavior

A

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

37
Q

Inhibitors

A

dec enzyme activity leading to a dec in metabolite prod
plasma levels of parent drug –> inc
clinical effect –> enhanced

*opp for prodrug

38
Q

Inducers

A

inc enzyme activity leading to increase in metabolite being made
plasma levels of parent drug –> dec
clinical effect –> diminished

*opp for prodrug

39
Q

Important routes of drug administration

A 
Oral (P.O.) 
Parenteral 
-subcutaneous (SC)
-intramuscular (IM)
-intravenous (IV)
40
Q

Bioavailability

A

Fraction of drug absorbed systemically after extravascular vs. intravascular admin (F)

F=AUC(oral)/AUC(IV)

> 0.90 –> Better
0.02 –> crappy

41
Q

Reasons for low bioavailability

A 
Poor absorption
Pre-systemic extraction (first-pass metabolism) 
-hepatic
-enteric (CYP3A)
Efflux transport (P-glycoprotein)
42
Q

Two most common pharmacokinetic drug interactions

A

Absorption (binding/chelation vs pH related)

Metabolism (induction vs inhibition)

43
Q

Aminoglycoside Kinetics (eg, gentamicin, tobramycin, amikacin)

A

Not absorbed orally

Poor lipid solubility
Little protein binding
Vd usually around 0.3 L/kg (low)

Metabolism - none

Excretion - primarily renal

44
Q

Genetic polymorphisms

A

SNPs *frequent, don’t prod change usually

Indels *infrequent but higher likelihood of having functional effect

45
Q

CYP450 polymorphisms

A 
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
46
Q

Whole gene polymorphisms

A

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

47
Q

Consequences of being poor metabolizer

A 
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
48
Q

Genetic changes that lead to impaired warfarin metabolism

A

CYP2C9 (pharmacokinetic) or VKORC1 (pharmacodynamic, responsible for clotting factor activation) alterations

60% of variability still explained by other factors (age, weight, comorbidities, etc)

49
Q

If HLA genetic change involved… greater risk for

A

alergic rxn

would req pharmacogenetic testing

50
Q

Barriers to pharmacogenetics testing in clinical practice

A

Resistance to abandon “trial & error” approach

Concern about genetic discrimination

Unfamiliarity with principles of genetics

Lack of outcomes data

Affordability

51
Q

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

A

Clearance

Emma II (24 decks)

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