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OU PDA > Exam 4 > Flashcards

Exam 4 Flashcards

1
Q

What yields the biological response?

A

signal transduction and signal amplification

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2
Q

How should a receptor be named?

A

after the endogenous agonist

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3
Q

What is the law of mass action?

A

rate of chemical reaction is proportional to the product of the concentrations of reactants

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4
Q

K(D)

A

equilibrium dissociation constant for the drug from the receptor

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5
Q

With respect to the law of mass action, what are things we have to assume?

A
  • Magnitude of the effect is proportional to the amount of receptors bound or occupied
  • Emax occurs when all receptors are bound
  • Binding of the drug to the receptor exhibits no cooperativity (no allosteric binding)
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6
Q

define pharmacophore

A

portion of a drug that is responsible for its biological action

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7
Q

define affinity

A

the strength of the interaction/binding between the ligand and its receptor

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8
Q

Kd

A

concentration of drug required to occupy 50% of available receptor sites

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9
Q

Bmax

A

maximum number of receptors that can be bound by drug

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10
Q

K(A)

A

affinity; = 1/Kd

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11
Q

Define threshold concentration

A

minimum concentration required to elicit a measurable response

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12
Q

What does “ceiling effect” mean?

A

when Emax is reached; doesn’t matter how much drug you add, you will not see a response

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13
Q

Define potency

A

A measure of the amount of drug necessary to produce an effect of a given magnitude; consider EC50

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14
Q

Define efficacy

A

ability of drug to elicit response by binding to a receptor; consider Emax

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15
Q

What is intrinsic efficacy / activity?

A

describe the ability of a drug to activate a receptor after the drug-receptor complex has formed

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16
Q

What happens after a receptor gets activated?

A

-> 2nd messengers -> signal transduction cascade of events to produce the biologic effect

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17
Q

What is an agonist?

A

a molecule that binds to a receptor to activate it

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18
Q

What is an antagonist?

A

a molecule that binds to a receptor to prevent further binding

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19
Q

What is an inverse agonist?

A

a molecule that binds to an activated receptor and turns it inactive

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20
Q

Characteristics of an antagonist

A
  • high affinity
  • binds even in absence of agonist
  • low dissociation
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21
Q

Two mechanism for irreversible antagonism

A
  • bind covalently to active site of receptor

- bind to allosteric site

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22
Q

What are functional / physiological antagonists?

A

works on different receptors but physiological effects are opposite => cancel each other out

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23
Q

What are chemical antagonists?

A

antagonist that prevents binding of agonist by disturbing the molecule itself from binding

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24
Q

What are the ways in which chemical antagonists can take action?

A
  • combine with inorganic substances

- combine with macromolecules

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25
Q

What are examples of physically active agents?

A
  • magnesium sulfate
  • mannitol
  • hydrogen peroxide
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26
Q

What are pharmacokinetic antagonists?

A
  • drug-drug interaction

- absorption of drug is decreased or metabolism and excretion of drug are increased

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27
Q

There were several examples of tolerance with pharmacotherapeutic agents. What were they?

A
  • slow regeneration of inactive receptor
  • formation of endogenous inhibitor
  • negative cooperativity
  • phosphorylation of receptor; uncoupling
  • “down-regulation”; receptor internalization
  • depletion of endogenously released factor
  • increased metabolism to inactive form
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28
Q

Define desensitization

A

Receptors show a reduced ability to be activated again by their respective drug

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29
Q

What are the stages of GPCR desensitization?

A
  • Phosphorylation
  • Internalization
  • Down-regulation (Degradation)
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30
Q

How does desensitization work?

A
  • Clathrin-coated pit engulfs drug-receptor complex
  • Goes to early and late endosome
  • Goes to lysosome to be broken down
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31
Q

Can resistance be a heritable change?

A

Yes, it generally is

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32
Q

What does rifampin target?

A

RNA polymerase

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33
Q

How can you reduce threshold of intrinsic resistance with respect to rifampin targeting fungi?

A
  • administer rifampin with low concentration of polyene

- it weakens the membrane which allows rifampin to get into the cell

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34
Q

What are some mechanisms for antibiotic resistance?

A
  • alteration of target
  • degradation of drug
  • efflux of drug
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35
Q

What are the mechanism of resistance to β-lactams?

A
  • porin mutation

- production of β-lactamase

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36
Q

Describe combination chemotherapy

A
  • two drugs that target the same pathway
  • one drug helps the other drug take effect
  • one drug decreases resistance of the therapeutic drug
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37
Q

Define transformation

A

cells take up small bits of DNA and incorporate them into the chromosome

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38
Q

Define transduction

A

bacteriophage mediated transfer of resistance determinants

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39
Q

Define conjugation

A

cell-cell contact mediated transfer of genetic material

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40
Q

What are the mechanisms of resistance with respect to gene transfer?

A
  • transformation
  • transduction
  • conjugation
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41
Q

What are the mechanisms of resistance with respect to gene amplification?

A
  • spontaneous duplication of essential gene
  • over-production of ligand to overcome competitive inhibition
  • mutation in molecule to alter drug-complex binding
  • altered transport of drug into the cell
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42
Q

What are the mechanisms of resistance with respect to biochemical processes?

A
  • inhibit bacterial protein synthesis
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43
Q

What is the TET protein?

A

pumps drug out of cell; slow in normal bacteria but produced a lot by resistant isolates

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44
Q

How does tetracycline get inside the cell?

A
  • crosses outer membrane via passive transfer

- crosses inner membrane via active uptake

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45
Q

How does methotrexate get into the cell?

A
  • at low concentrations, by energy dependent carriers

- at high concentrations, by passive diffusion

46
Q

How do you treat cancer with methotrexate? (with respect to dose)

A
  • give a high concentration so that passive diffusion into cell can happen
  • rescue normal cells with folate analogue Leucovorin since cancer cells do not have (DHF?)
47
Q

What are two drugs that cancer cells are resistant to?

A
  • vincristine

- actinomycin D

48
Q

How can cancer cells be resistant to drugs?

A
  • P170 or P-glycoprotein

- overproduction of transporter -> drug efflux

49
Q

What are examples of inactivation of drug?

A
  • β-lactamase inactivation of penicillins
  • Enzymatic modification of aminoglycosides
  • Enzymatic modification of chloramphenicol
50
Q

How can you have sulfonamide resistance?

A
  • overproduction of metabolite PABA

- loss in feedback inhibition

51
Q

How can you have resistance to flucytosine?

A
  • loss of cytosine deaminase activity

- loss of feedback inhibition

52
Q

How does flucytosine work?

A

converted to fluorouracil by cytosine deaminase

53
Q

What is the purpose of autolysins?

A
  • mutant cells contain autolysins

- makes bacteriostatic drug -> bacteriocidal

54
Q

What are the characteristics of a “normal” patient?

A
  • 18-65 years old
  • weighs 70kg
  • have normal body functions
55
Q

What are types of therapeutic variability?

A
  • gene difference
  • Pharmacokinetic
  • Pharmacodynamic
56
Q

Characteristics of infants

A
  • increased permeability
  • greater %age of water
  • decreased biotransformation; underdeveloped metabolic enzymes
  • decreased renal clearance; reduced GFR
  • lower rate of blood flow to most organs
57
Q

Characteristics of the elderly

A
  • decline in organ function
  • absorption decreased compared to metabolism and excretion
  • decreased liver and renal blood flow
  • reduced # of nephrons
  • increased sensitivity to drugs
58
Q

Hormones that are secreted in the morning

A

cortisol, catecholamines, angiotensin and aldosterone

59
Q

Hormones that are secreted at night

A

gastric acid, growth hormone, folliclestimulating hormone

60
Q

Why does asthma symptoms get worst at night?

A

lowest levels of cortisol (antiinflammatory) and high levels of histamine (bronchoconstrictor)

61
Q

Which drugs increase gastric emptying?

A
  • phenytoin

- morphine

62
Q

Which drugs decrease gastric emptying?

A

erythromycin

63
Q

What effect does the normal flora have on effects of specific drugs that we talked about in class?

A
  • converts digoxin into a more polar form; more excretd

- converts oral contraceptives into more lipophilic form to allow more to be reabsorb

64
Q

What happens if you lower urine pH?

A
  • pH lowered by ammonium chloride

- increases excretion of antihistamines and amphetamines

65
Q

What happens if you increase urine pH?

A
  • pH increased by sodium bicarbonate

- increases excretion of ASA and phenobarbital

66
Q

Tubular secretion can be altered. Give a specific example in class that we discussed.

A

Probenecid (weak acid) blocks clearance of other drugs like penicillins and sulfonamides

67
Q

Describe the tyramine drug-food interaction

A
  • tyramine is found in cheese and drinks
  • antidepressants reduce tyramine metabolism
  • increased tyramine can lead to elevated NE
  • can cause hypertensice crisis
68
Q

What is an idiosyncratic response?

A
  • highly unusual and unpredictable response in an individual
  • can be caused by enzyme deficiency
69
Q

Define Pharmacogenetics

A

study of one gene as it relates to drug response

70
Q

Define Pharmacogenomics

A

study of genome as it relates to drug response

71
Q

What are the mechanisms for succinylcholine apnea?

A

have an abnormal amount of cholinesterase -> increased amount of succinylcholine -> prolonged muscle relaxation and apnea

72
Q

How can you test levels of cholinesterase?

A

administering dibucaine in vitro

73
Q

N-acetyltransferase (NAT) 1

A

metabolizes p-aminosalicylate and paminobenzoic acid

74
Q

N-acetyltransferase (NAT) 2

A
  • metabolizes isoniazid and other antiinfectives, caffeine

- slow and rapid acetylators

75
Q

CYP2D6

A

responsible for the metabolism of ~25% of drugs

  • 70 variant alleles
  • Prozac inhibit this enzyme activity
76
Q

CYP2C9

A
  • primary pathway for metabolism of warfarin

- variants (2and3) are associated with excessive anticoagulation

77
Q

Thiopurine Biotransformation

A
  • XO and TPMT converts TP into non-toxic form
  • HPRT converts it to toxic form
  • normal dosing depends on how much gets converted to toxic form
78
Q

How does Chronic Myeloid Leukemia come about?

A
  • BCR-ABL fusion gene from chromosome 22 and 9 respectively
  • treated with Imatinib (Gleevec) which inhibits cell division in the CML clones but does not affect growth of normal cells
79
Q

How does cystic fibrosis come about?

A
  • CFTR mutation; improper folding in ER

- treated by stabilizing misfolded proteins

80
Q

How many percent of the genome actually codes for proteins?

A

1%

81
Q

Define mutation

A
  • permanent, structural change in the DNA

- the types are: insertions, duplications, single base substitution

82
Q

Define polymorphism

A
  • a gene that has more than one allele

- alleles that are present in at least 1% of the population

83
Q

GWAS

A
  • Genome Wide Association Study

- comparing DNA profiles with and without diseases to target locations of susceptible genes

84
Q

Define haplotype

A

Segments of chromosomal DNA that usually remain intact during inheritance because they have not been broken up by meiotic recombination

85
Q

Iressa

A
  • used for non-small-cell lung cancer patients
  • target protein is EGFR (epidermal growth factor receptor)
  • mutations in EGFR can increase therapeutic effects
86
Q

Define innate tolerance

A

tolerance which cannot be controlled

87
Q

What are the types of learned tolerance?

A
  • Behavioral tolerance

- Conditioned tolerance

88
Q

Conditioned tolerance

A

Body’s physiology reacts to the environment.

89
Q

What are the types of acquired tolerance?

A
  • Pharmacokinetic tolerance
  • Pharmacodynamic tolerance
  • cross tolerance
90
Q

How does pharmacokinetic tolerance happen?

A
  • Body increases metabolism as a response to the drug.

- Tolerance by administering the same drug or other drugs.

91
Q

How does pharmacodynamic tolerance happen?

A

Changes in receptor density, signaling pathway, and efficiency of the drug.

92
Q

How does cross tolerance happen?

A

develops from repeated administration of another drug

93
Q

What is the reward pathway?

A
  • mesolimbic dopaminergic system in the brain

- causes addiction

94
Q

What are the most common drugs of abuse?

A
  • Opiates and narcotics
  • CNS depressants
  • CNS stimulants
  • Hallucinogens
  • Marijuana (Tetrahydrocannabinol)
95
Q

GABA

A

inhibits release of dopamine from neurons

96
Q

Opiates mechanism of action

A

inhibits GABA

97
Q

Benzodiazepines and Alcohol mechanism of action

A

causes ion channels to open -> increase intracellular Ca2+ -> cause vesicles to be released into synaptic cleft

98
Q

Cocaine and Amphetamine mechanism of action

A

breakdown transporter that reuptakes dopamine

99
Q

What are the drugs used for therapy of drug addiction / overdose to opiates?

A
  • methadone
  • buprenorphine
  • naltrexone
100
Q

What are the drugs used for therapy of addiction / overdose to alcohol?

A
  • disulfiram
  • acamprosate
  • naltrexone
  • topiramate
101
Q

What are the drugs used for therapy of addiction / overdose to tobacco?

A
  • nicotine preparations
  • varenicline
  • bupropion
102
Q

With respect to drug discovery, what is a lead?

A

a compound of interest

103
Q

What are the compound-based approach?

A
  • naturally occurring products
  • purely synthetic drugs
  • drug metabolites
104
Q

What are the target-based approach?

A
  • systemic approach to identifying targets

- screening method

105
Q

How long does toxicity tests be done for?

A

for two years in two species: rodent and non-rodent disease model

106
Q

What needs to be approved before clinical trials?

A

investigational new drug

107
Q

What happens after application of IND?

A

FDA’s Center for Drug Evaluation and Research (CDER) decides within 30 days

108
Q

Define priority drugs

A

Drugs that may be expedited if it considered a special and medical need

109
Q

Define accelerated or fast-track drugs

A

Fast review of drugs that treat life-threatening diseases

110
Q

Define orphan drugs

A

drugs that treat conditions which fewer than 200k people have

111
Q

What process do generic drugs undergo?

A

ANDA = abbreviated new drug application

OU PDA (8 decks)

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