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Neuro 2 Exam 1 > Biotransformation, Pharmacogenomics, Clinical Trials > Flashcards

Biotransformation, Pharmacogenomics, Clinical Trials Flashcards

1
Q

Types of drugs that are eliminated through renal excretion:

-characterisitcs

A

polar compounds or compounds with small molecular volumes

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2
Q

What drug route does not undergo first pass effect

A

parenteral route administrated drugs: non-oral drugs

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3
Q

Phase I vs Phase II reactions result in?

A

phase 1 results in biological inactivation of the drug while phase II reactions produce a metabolite with improved water solubility and increased molecular weight.

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4
Q

Phase I reaction types

  • more common
  • less common
A

more common is oxidation, reduction, and hydrolysis

less common includes hydroxylation, epoxidation, dealkylation, deamination, desulfuration, dechlorination

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5
Q

Enzymes that carry out phase I reactions

(x3)

A

Cytochrome P450s, Flavin-containing monooxygenases, epoxide hydrolases

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6
Q

where are phase I enzymes located?

phase I products vs parent drug?

A

phase I enzymes are located in the lipophlic ER membranes of the liver

products are generally more reactive and may be more toxic than the parent drug

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7
Q

Phase II rxns

  • characteristics of drug conjugates produced
  • conjugation dependent on which endogenous substrates?
  • rate of conjugation vs phase I rxns?
A
  • drug conjugates are polar molecules w/ higher molecular weight that are readily excreated and often inactive compared to their precursors
  • dependent upon endogenous substrates such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid
  • conjugation occurs at faster rates than phase I
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8
Q

Most important CYPs:

  • (x5)
  • which is the most common?
A

CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A4

CYP3A4 is the most abundantly expressed

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9
Q

how does a CYP work?

-use molecular oxygen (O2) and H+ derived from what?

A

-use O2 and H derived from the cofactor reduced nicotinamide adenine dinuleotide phosphate (NADPH) to carry out the oxidation of substrates

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10
Q

Genetic defect in pseudocholiesterase causes?

A

that individual to metabolize SUCCx at 50% of normal

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11
Q

Slow acetylator phenotype:

  • have decrease what levels?
  • what types of drugs metabolized slower?
  • what populations is this common in?
A
  • AR trait leads to decrease in N-acetyltransferase levels
  • isoniazid (TB drug), hydralazine (HTN), caffeine, other amines, metabolized slower and can lead to hepatotoxicity (hepatitis)
  • phenotype occurs in about 50% of US population, 83% Frenchies, less common in Asians
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12
Q

Enzyme induction:

-examples

A

phenytoin, chronic ETOH (CYP2E1), aromoatic hydrocarbons like benzo[a]pyrene, rifampin, phenobarbital, other barbituates

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13
Q

newborns have trouble metabolizing hemoglobin why?

A

immature hepatic metabolic pathways–> newborns unable to conjugate bilirubin with UDP glucuronic acid and bilirubin is unable to be excreted

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14
Q

Acetaminophen toxicity

A
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15
Q

Define pharmacogenomics

A

study of the entire genome to assess multigenetic determinants of drug response

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16
Q

Define Single Nucleotide Polymorphism

A

variation in DNA sequence that is present at an allele frequency of 1% or greater in a population

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17
Q

G6PD deficiency

  • MOA of G6PD
  • deficiency leads to?
A

MOA: G6PD produces NADPH which regenerates glutathione from its oxidized form

-reduced glutathione protects cells against oxidative stress/damage, so without it oxidative damage leads to hemolytic anemia in the presence of oxidants

18
Q

OATP1B1

  • what does it do?
  • what mutation associated w/ reduced membrane expression?
  • pts w/ this defect can suffer from _ induced myopathy
A
  • organic Anion Transporter (OATP1B1) responsible for hepatic uptake of weak acidic drugs
  • Val74Ala mutation is associated w/ reduced membrane expression–>reduced trafficking
  • pts with this mutation suffer from Simvastatin-induced myopathy
19
Q

Enzyme responsible for converting codeine to morphine

A

CYP2D6

20
Q

Enzyme responsible for activation of Clopidogrel

-polymorphisms cause?

A

CYP2C19

decreased activity of the drug causing increased risk for adverse CV events. specifically the CYP2C19*2 gene

21
Q

N-acetyltransferase genetic variation:

-causes problems w/ which drug

A

causes hepatitis w/ isoniazid

22
Q

TPMT, 6-mercaptopurine

-responsible for deactivation of?

A

responsible for deactivation of thiopurine drugs, 6-mercaptopurine can cause defects in TPMT fxn

23
Q

UGT1A1

  • responsible for ?
  • mutations lead to?
A

conjugates glucuronic acid so it can be excreted into bile

UGT1A1-28 mutations lead to increased risk of adverse drug rxns due to reduced biliary elimination

24
Q

Variations associated w/ altered response to warfarin therapy

A
  • VKORC1 results in increased sensitivity to warfarin/ increased bleeding
  • CYP2C9 polymorphism results in decreased metabolic clearance of S-Warfarin leading to increased anticoagulation and bleeding
25
Q

What is a lead compound?

A

chemical compound that has pharmacological or biological activity and whose chemical structure is used as a starting point for chemical modifications in order to improve potency, selectivity, and phamacokinetic parameters.

26
Q

no-effect dose

A

maximum dose at which a specified toxic effect is not seen, just lower than the threshold of harmful effects

27
Q

In vitro cell based study vs in vivo

A

in vitro–> lead compounds tested in mammalian cells to see which proteins the drug binds to and/or which pathways it may inhibit or upregulate

in vivo–> drugs tested in mammalian subjects, animals first and then humans

28
Q

goals of preclinical testing:

(x3)

A
  • identify potential human toxicities without human testing
  • design tests to further define the toxic mechanisms
  • predict the specific and most relevant toxicities to be monitored in clinical trials
29
Q

Limitations of preclinical testing

(x4)

A
  • time and cost–> could take 2-6 years
  • number of animals used–> cost of mice
  • extrapolation of values–> not all toxicities directly translate to humans from animals
  • rare and adverse events are unlikely to be detected in preclinical animal testing
30
Q

Caveats in human testing

(x3)

A
  • variable natural history and proggression of disease (diseases can increase and decrease in severity over time or spontaneously disappear)
  • presence of other diseases and risk factors (other drug use can affect results)
  • subject and observer bias

(placebo effect)

31
Q

Double blind

A

neither the patient nor the physician knows the identity of the therapy the pt is receiving

32
Q

single blind

A

only the health professional knows the identity of the therapy the pt is receiving

33
Q

open label

A

both the patient and health professional know the identity of the therapy the pt is receiving

34
Q

parallel trial

A

a study where one group of pts receives only treatment A and the other group of pts receives only treatment B

35
Q

Crossover trial

A

pts receive each therapy in sequence so that the pts serve as their own controls

36
Q

Endpoint vs surrogate endpoint

A

endpoint: the primary outcome measure

surrogate endpoint: an endpoint that may correlate with the “real” endpoint but does not necessarily have a guaranteed relationship.

37
Q

Phases of clinical trials

phase 0, phase 1

A

0: subpharmacological doses of prospective drug candidates are administered to human colunteers–> provides early pharmacokinetic data in humans
1: conducted to determine whether humans and animals show different responses to the investigational drug and establish approximate limits on the safe dosage range

38
Q

phases of clinical trials

phase 3

A

performed on large groups (100-200) that have the target disease to determine its efficacy, dosing requriements, and toxicities

39
Q

phases of clinical trials

A

only occurs after approval of a drug to go to market

post marketing study to continue to monitor safety and efficacy of the drug

40
Q

Investigational new drug:

  • define
  • must contain
A

an application that must be approved before the drug is transported across state lines

-must contain preclinical data from animal pharmacology and toxicology studies, manufacturing info, clinical protocols, and investigator info

41
Q

institutional review board:

-what does it assure

A

assures appropriate steps are taken to protect the rights, safety, and welfare of humans participating as subjects in the research.

42
Q

new drug application:

-define

A

an application filed with the FDA by a manufacturer of a drug for a license to market the drug for a specific indication.

Neuro 2 Exam 1 (7 decks)

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