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Pathophysiology, Pharmacology, and Therapeutics > Exam 3 Concepts > Flashcards

Exam 3 Concepts Flashcards

1
Q

location of DNA replication

A

nucleus

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2
Q

location of DNA transcription

A

nucleus

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3
Q

location of DNA translation

A

cytoplasm

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4
Q

genes

A

information-containing elements in DNA

passed on to daughter cells when cell divides

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5
Q

deoxyribonucleic acid

A

DNA

store genetic information

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6
Q

of genes in human genes

A

25,000

3 billion base pairs

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7
Q

of chromosomes in human genes

A

23

22 autosomes

1 sex chromosome

(46/cell)

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8
Q

nucleotides

A

building blocks of all nucleic acids

3 components covalently bound together

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9
Q

3 components of nucleotides

A

sugar (ribose)

nitrogen-containing base

1-3 phosphate groups

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10
Q

bases of nucleotides

A

adenine - adenosine thymine - thymidine cytosine - cytidine guanine - guanosine uracil - uridine

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11
Q

adenosine

A

many fxns in dephosphorylated or phosphorylated forms

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12
Q

purines

A

adenine

guanine

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13
Q

pyrmidine

A

cytosine

thymine

uracil (RNA)

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14
Q

absence of oxygen atom at 2’ carbon in DNA

A

makes it highly stable

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15
Q

synthesis of DNA/RNA

A

phosphodiester bond formed between phosphate group on 5’ carbon of one nucleotide and hydroxyl group on 3’ carbon of next nucleotide

forms sugar-phosphate backbone

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16
Q

backbone of ladder

A

sugar-phosphate bonds

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17
Q

rungs of ladder

A

double stranded DNA held by hydrogen bond

2 bonds between A and T

3 bonds between G and C

complementary and antiparallel

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18
Q

double helix

A

one complete turn every 10 pairs

complementary and specific

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19
Q

organization of DNA

A
  • nucleosomes
  • chromatin
  • euchromatin
  • heterochromatin
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20
Q

nucleosomes

A

DNA packaged in nucleus associated with histones (basic proteins)

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21
Q

chromatin

A

DNA + histone complex

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22
Q

euchromatin

A

actively transcribed genes

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23
Q

heterochromatin

A

inactive segments

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24
Q

compaction of DNA

A

1 meter of DNA compacted into a micrometer - due to compaction into chromatin

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25
Q

DNA replication is semiconervative

A

each new DNA molecule has one parental strand and one new daughter strand identical strands - one acting as a template for the other

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26
Q

high fidelity of DNA synthesis

A

1 in 1 billion nucleotides (1 x 10^9)

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27
Q

DNA polymerase enzyme

A

first proofreading, before nucleotide is incorporated

self-correction by exonucleolytic proofreading - DNA polymerase III adds mismatched base, notices the mistake, and corrects it strand mismatch repair

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28
Q

efficient error correction

A

in 5’-3’ direction (3’ end does not serve well as template, which is why RNA error is more often)

critical to reduce mutations - associated with cancer

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29
Q

DNA replication

A
  • DNA polymerase uses dNTPs as building blocks
  • can only extend pre-existing strand replication
  • initiated at ori (origin) site, multiple origins
  • chromosome direction: 5’-3’
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30
Q

replication complex includes:

A
  • DNA polymerases
  • primase
  • helicase
  • SSB proteins
  • topoisomerase
  • ligase
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31
Q

DNA repair

A
  1. normal DNA
  2. DNA damage
  3. removal of damaged base
  4. DNA polymerase inserts new base using good strand as a template
  5. DNA ligase repairs nick
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32
Q

End Problem in DNA replication

A

newly synthesized lagging strand has a gap of about 1000 bases at its 5’ end (not enough space for replication complex to bind) with progressive cell divisions, this “gap” starts to eat into the chromosome, causing the cell to die

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33
Q

telomere

A
  • complex of noncoding DNA and protein at ends of linear chromosomes
  • maintain structural integrity of chromosomes
  • solve ‘end problem’ of linear chromosomes
  • several thousand tandem repeats of AGGGTT
  • “mitotic clocks” whose length is inversely proportional to the number of times the cell has divided - cell division will cease when telomere becomes too short
  • ex: PTSD can speed up this process
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34
Q

telomerase enzymes

A

reverse transcriptase maintains telomeric length

only present in germ cells, stem cells, cancer cells (immortality of cancer cells)

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35
Q

promoter

A

base-pair sequence that specifies where transcription begins

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36
Q

RNA coding sequence

A

base-pair sequence that includes coding information for polypeptide chain (protein - although not yet in final form) specified by gene

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37
Q

terminator

A

sequence that specifies end of the mRNA transcript

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38
Q

sequence of gene –> protein

A
  • DNA
  • pre-mRNA (exons and introns)
  • mRNA (introns removed)
  • polypeptide
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39
Q

DNA transcription

A

master blueprint encoded by DNA is expressed through RNA - working copies

mRNAs translated into proteins; other RNAs perform structural, regulatory, catalytic fxns

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40
Q

selectivity of DNA transcription

A

signals in DNA that instruct RNA polymerase when, how often to start, and when to stop

regulatory proteins involved in selectivity

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41
Q

introns

A

can code for several regulatory sequences

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42
Q

RNA

A
  • sugar molecule = ribose
  • uracil replaces thymine
  • single-stranded
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43
Q

RNA transcription steps

A
  • initiation
  • elongation
  • termination
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44
Q

RNA polymerase

A
  • can initiate de novo synthesis
  • lacks proofreading capability
  • error rate = 1 X 10^4
  • uses NTPs
  • transcription initiated at promoter, stops at terminator sequence
  • initiation requires transcription factors
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45
Q

promoter element of RNA

A

provides directionality to RNA polymerase and dictates which DNA strand is used as template

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46
Q

transcription factors

A
  • proteins that regulate transcription bind promoter
  • recruit RNA polymerase to promoter
  • mediate response to signals
  • modulate frequency of initiation
  • respond to signals such as hormones, GFs, cytokines
  • regulate temporal gene expression
  • recruit co-activators such as HAT involved in chromatin remodeling
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47
Q

enhancer DNA sequences

A

bind enhancer-binding proteins (TFs) which greatly increase rate of transcription

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48
Q

types of RNA

A
  • mRNA
  • rRNA
  • tRNA
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49
Q

mRNA

A

most genes in a cell transcribed to mRNA which direct synthesis of proteins

3-5% of RNA in cell

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50
Q

rRNA

A

form core of ribosomes

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51
Q

tRNA

A

adaptors in protein synthesis

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52
Q

RNA translation

A

process by which mRNA is used to direct synthesis of a protein - in cooperation with tRNA and ribosomes

mRNA may serve as template for thousands of proteins before it degrades

read linearly, from one end to another

each set of 3 nucleotides serve as codon for each particular amino acid

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53
Q

mRNA codons

A

do not direclty recognize amino acids; tRNA as translator is required anticodon at one end

amino acid attachment at other

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54
Q

tRNA structure

A

anticodon formed by 3-nucleotide sequence

recognition between mRNA codon and tRNA anticodon with complementary base pairing

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55
Q

why is DNA read 5’-3’

A

sequence is different - would code for different amino acid sequence/protein

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56
Q

ribosomes

A
  • large complexes of proteins and RNA assembled in nucleolus
  • find starting place on mRNA
  • line up tRNA on mRNA
  • set correct reading frame for codon triplets
  • catalyze peptide bonds that hold together amino acids
  • newly synthesized protein chain released from ribosome when it reaches stop codon
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57
Q

genetic code is a triplet code

A
  • codon = 3 mRNA nucleotides
  • 64 codons total
  • 60 mRNA triplets for 19 amino acids, 3 for “stop”, 1 for methionine (start)
  • most amino acids coded by more than one triplet, but each tripled linked to only one amino acid
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58
Q

AUG

A

methionine - start code

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59
Q

UAA, UAG, UGA

A

stop codons

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60
Q

phosphorylation

A

addition of a phosphate (PO4) group, necessary for activation/inactivation of protein

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61
Q

glycoslyation

A

addition of a sugar moiety, necessary for proper folding, fxn

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62
Q

hydroxylation

A

addition of hydroxyl (OH) group, affects folding of collagen

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63
Q

fatty acylation

A

addition of fatty acid groups (palmitoyl, myrisyl), crucial for membrane localization of protein

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64
Q

chaperones

A

aide protein folding to achieve functional form

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65
Q

primary protein structure

A

coded by gene

linear amino acid sequence held together by peptide bonds

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66
Q

secondary protein structure

A

held together by H-bonds between peptide groups

a-helix and B-pleated sheet

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67
Q

tertiary protein structure

A

interactions between amino acid side chains; ionic bonds; H-bonds; hydrophobic attraction forces; disulfide bonds

dictates fxn of protein

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68
Q

quaternary protein structure

A

3D structure of multi-subunit protein

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69
Q

transcription to final protein - summary

A
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70
Q

allele

A

variant of gene sequence

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71
Q

heterozygous

A

different alleles at a given locus

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72
Q

homozygous

A

same allele at given locus

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73
Q

locus

A

place where particular gene is located on chromosome

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74
Q

phenotype

A

observable properties; physical manifestations

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75
Q

genotype

A

genetic makeup with reference to particular trait

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76
Q

dominant allele

A

allele that is phenotypically expressed when homozygous or heterozygous

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77
Q

recessive allele

A

allele that is phenotypically expressed only when homozygous

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78
Q

penetrance

A

how many people carrying the disease allele actually have the disease (population-based characteristic)

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79
Q

expressivity

A

degree to which a genotype is expressed phenotypically in individuals - severity of disease

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80
Q

mutation

A
  • change in DNA sequence at particular locus
  • frequency >1% in population
  • low frequency due to efficient DNA repair mechanisms
  • single-stranded breaks: easily repaired
  • double-stranded breaks: possible permanent loss of genetic information at break point
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81
Q

potential mutagens

A
  • radiation
  • chemicals
  • viruses
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82
Q

point mutation

A

single base pair substitution

may cause affected codon to signify abnormal amino acid

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83
Q

frameshift mutation

A

addition/removal of one or more bases - changes “reading frame”

alters primary structure of protein

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84
Q

missense point mutation

A

wrong amino acid is made i.e. sickle-cell anemia (Val for Glu)

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85
Q

nonsense point mutation

A

stop codon inserted

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86
Q

silent mutation

A

same amino acid is made

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87
Q

duplication mutation

A

a few bases or chunks of chromosomes duplicated causes inactivation or over-activation of genes

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88
Q

deletion mutation

A

a few base or chunks of chromosome deleted

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89
Q

inversion mutation

A

chunks of chromosome inverted

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90
Q

translocation mutation

A

pieces of chromosomes exchanged between non-homologous chromosomes

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91
Q

Mendelian Single-Gene disorders

A
  • alterations/mutations of single genes affected genes code for abnormal enzymes, structural/regulatory proteins,
  • regulatory RNA classification: location: autosomal or sex
  • mode of transmission: dominant or recessive
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92
Q

autosomal dominant disorders

A
  • mutation of specific autosomal gene
    • 1 mutant allele sufficient for disease phenotype
    • males/females equally affected
    • usually 1 affected parent
    • unaffected individuals do not transmit disease
    • offspring of 1 affected parent: 1 in 2 chance
    • offspring of 2 affected parents: 3 in 4
    • penetrance and expressivity vary in individuals
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93
Q

autosomal recessive disorders

A
  • mutation of recessive autosomal gene
  • males/females equally affected
  • usually not apparent in parents; both parents are carriers
  • unaffected individuals may transmit to offspring
  • two carriers have 1/4 chance of having affected offspring and 2/4 chance of having carrier offspring
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94
Q

sex-linked (x-linked) disorders

A
  • mutation of sex chromosome (almost always X)
  • nearly all recessive
  • females express when they have BOTH (rare)
  • males always express (only one X)
  • affected fathers transmit defective gene to all daughters, but not to sons
  • carrier female has 1/2 chance of producing affected son or carrier daughter
  • females affected: homozygous from carrier/affected mother and affected father ex: hemophilia A
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95
Q

polygenic and multifactorial disorders

A
  • run in families
  • more common than single gene disorders
  • interaction of several genes: polygenic
  • range of severity
  • difficult to predict based on family history
  • interaction of several genes and environment: multifactorial
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96
Q

tumor or neoplasm

A

“new growth” - abnormal mass of tissue benign or malignant (cancer)

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97
Q

cancer associated with

A

altered expression of cellular genes

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98
Q

benign vs. malignant tumor

A
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99
Q

malignant phenotype

A
  • arises due to loss of control of cell number
  • increase proliferation
  • reduced death cells lose differentiated features and contribute poorly to tissue fxn
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100
Q

1/3 of cancer-related deaths due to

A
  • tobacco use
  • nutrition
  • obesity
  • sun exposure
  • sexual exposure to HPV
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101
Q

tobacco use in cancer

A

two types of carcinogens: initiator (genetic damage) and promoter (tumor growth)

tobacco contains both

second-hand smoke

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102
Q

nutrition in cancer

A

dietary factors:

  • fat
  • alcohol
  • fiber
  • antioxidants

suggestions: -

  • limit excessive calorie/alcohol intake
  • increase dietary fiber, fruit, veggies
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103
Q

genetic mechanisms of cancer

A

mutations

acquired (somatic)

inherited (germline)

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104
Q

sporadic cancer inheritance pattern

A

occurs by chance, not inherited.

95% of all cancers

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105
Q

hereditary cancer inheritance pattern

A
  1. autosomal dominant cancer syndromes
  2. autosomal recessive
  3. familial cancers; uncertain inheritance
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106
Q

autosomal dominant cancer inheritance pattern

A

tumor suppressor (ts) genes

  • single copy of inherited mutant gene increases cancer risk
  • autosomal dominant pattern of inheritance
  • children of mutation carriers have 50% risk of same mutation ex: retinoblastoma (Rb), Li-Fraumeni syndrome (p53)
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107
Q

cancer inheritance patterns

A
  • carriers of mutant Rb or p53 gene almost always develop cancer
  • clustering or rare, bilateral, multifocal cancers
  • incomplete penetrance and variable expressivity
  • associated w. specific mutation
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108
Q

autosomal recessive cancer inheritance pattern

A
  • DNA repair genes
  • genome instability
  • high rate of certain cancers ex: xeroderma pigmentosum, blood syndrome, fanconi anemia
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109
Q

familial cancers of uncertain inheritance (inheritance pattern)

A
  • early age of onset
  • predisposition to cancer
  • higher incidence of tumors in relatives
  • not associated with specific mutation ex: breast, ovary, colon
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110
Q

checkpoint

A

control point in cell cycle where “stop” or “go ahead” signals regulate cell cycle

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111
Q

GI checkpoint

A

restriction point: proceed with cell cycle or shunt to G0 oncogenes, pRB: check for…

  • cell size
  • nutrients
  • growth factors
  • DNA damange
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112
Q

G0 checkpoint

A

resting state

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113
Q

G2 checkpoint

A

ok to enter mitosis oncogenes: check for…

  • cell size
  • DNA replication
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114
Q

M checkpoint

A

spindle assembly checkpoint

check for: chromosome attachment to spindle

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115
Q

S checkpoint

A

DNA synthesis - p53

do or die

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116
Q

mutational events in cancer

A
  • subtle (point) or large (karyotypic) changes
  • epigenetic modifications
  • environmental agents, viruses, radiation
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117
Q

point mutations in cancer

A
  • small insertions/deletions can convert proto-oncogene to oncogene or inactivate a ts gene
  • in EGFR or RAS proto-oncogene: over-activates protein (gain of fxn)
  • in Rb or p53 (ts’s) reduces/abolishes fxn (loss of fxn)
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118
Q

large karyotypic changes in cancer

A
  1. translocations: exchange parts of nonhomologous chromosomes causing: overexpression of proto-oncogene, creation of novel fusion protein
  2. deletions: whole or portions of chromosome lost - loss of ts genes
  3. gene amplifications: several hundred copies of gene on chromosome - overexpression of normal proto-oncogene
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119
Q

epigenetic modifications in cancer

A

heritable, reversible changes in gene expression w.o mutation

due to changes in DNA methylation and chromatin organization

low DNA methylation - high expression euchromatin

highly expressed affected by nutrition, environmental factors

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120
Q

genes that drive cancer

A

proto-oncogenes

tumor suppressor genes

for cancer to occur: suppress tumor suppressor genes (ts) and turn on oncogenes

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121
Q

proto-oncogenes

A
  • accelerate cell growth and division
  • transformed into oncogenes by gain of fxn mutations

may be:

  • growth factors
  • growth factor receptors
  • cytoplasmic signaling molecules
  • nuclear txn factors
  • proteins in cell-cell or cell-matrix interactions
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122
Q

tumor suppressor (ts) genes

A
  • inhibit cell growth and division contributes to cancer when inactive
  • both copies inactivated when cancer develops
  • one can inherit defective copy (much higher risk for developing cancer)
  • Rb and p53 are important ts genes (others - DNA repair genes: BRCA1 and 2; apoptosis genes)
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123
Q

from proto-oncogene to oncogene

A
  • oncogenes introduced to host cell by virus proto-oncogene mutation to oncogene (point)
  • normal proto-oncogene over-active (translocation)
  • extra copies of proto-oncogene in genome (amplification)
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124
Q

Rb gene

A

normally “master brake” for cell cycle blocks/stops cell division:

  • binds trxn factors
  • inhibits factors from transcribing genes that initiate cell cycle inactivating mutation of Rb gene
  • removes restraint on cell division and replication occurs
  • retinoblastoma, osteosarcoma, lung cancers
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125
Q

p53

A
  • guardian of genome
  • most common ts gene defect identified in cancer cells
  • >50% human tumors lack fxnal p53
  • transcriptional factor for cell cycle and DNA repair genes cellular stress monitor
  • accumulates after stress
  • binds to damaged DNA and stalls division to allow DNA repair
  • may direct cell to apoptosis
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126
Q

how does HPV cause cervical cancer?

A

E6 and E7 viral proteins inactive Rb and p53

  • E7: binds to Rb so promoter is turned on and cell divides
  • E6: binds to p53, which degrades
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127
Q

BRCA1 and BRCA2 genes in cancer

A

tumor suppressor genes hereditary breast/ovarian cancer

HBOC syndrome family history and inherited defect in BRCA increases risk of breast cancer

  • mutations in the different genes can cause same disease
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128
Q

six hallmarks of cancer

A
  1. self-sufficiency in growth signals
  2. resist anti-growth signals
  3. tissue invasion and metastasis
  4. limitless replication potential
  5. sustained angiogenesis
  6. evading apoptosis
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129
Q

self sufficiency in growth signals in cancer

A
  • keep dividing
  • oncogenes mutation at any step in growth signaling pathway
  • growth factor
  • GF receptor
  • downstream signaling molecules
  • trxn factors
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130
Q

resisting growth inhibitory signals in cancer

A

don’t stop growing

inactivation of ts genes (p53 and/or Rb)

cell cycle checkpoints non-fxnal

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131
Q

resisting apoptosis in cancer

A

don’t die

balance of pro- and anti-apoptotic proteins perturbed

tumor more from reduced cell death than from increased proliferation

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132
Q

cell immortality in cancer

A

keep going

up-regulation of telomerase enzyme in 90% of tumors

133
Q

sustaining blood flow in cancer

A

feeding the tumor

stimulate factors that promote growth of blood vessels

134
Q

tissue invasion and metastasis in cancer

A

take over

several steps

  • process by which cancer cells escape tissue of origin and initiate new colonies of cancer in distance sites
135
Q

metastasis steps

A
  1. carried by blood or lymph
  2. invade surrounding tissue
  3. enter blood/lymph vessel
  4. carried to distant site
  5. escape lymph/blood vessel to surrounding tissue
  6. establish tumor
136
Q

mechanisms of metastasis

A
  1. loosening of intercellular jxns
  2. degradation
  3. attachment
  4. migration
137
Q

emerging hallmarks of cancer

A
  • altered energy metabolism
  • avoidance of immune detection
  • inflammation
  • genome instability
138
Q

multistep nature of carcinogenesis

A

initiation

promotion

progression

139
Q

initiation of carcinogenesis

A

initiating events:

  • genetic mutations (proto-oncogenes, ts genes)
  • proliferation: cancer development each cancer has own combo of mutations that lead to malignancy
140
Q

complete carcinogesn

A

can initiate cell damage

can promote cellular proliferation

141
Q

partial carcinogens

A

promoters that stimulate growth

incapable of causing genetic mutations

sufficient to singly initiate cancer

142
Q

promotion of carcinogenesis

A

stage during which mutant cell proliferates:

  • activate another oncogene
  • inactive ts gene
  • nutritional factors
  • infection regulated by many hormonal growth factors (may act as promoters for cancers)
  • estrogen
  • testosterone cancer cells produce telomerase
  • immortality
143
Q

progression in carcinogenesis

A

mutant, proliferating cells exhibit malignant behavior

change in structure, cell-cell attachment

secrete lytic enzymes evolved tumor cells differ from normal tissue significantly

144
Q

angiogenesis

A

process by which cancer tumor forms new blood vessels in order to grow

late stages of development

-triggers not well understood

inhibition of angiogenesis is an important therapeutic goal

145
Q

cancer therapy

A

early detection = best prognosis

146
Q

mainstays of cancer therapies

A

surgery

radiation

drug/chemo

147
Q

emerging cancer therapies

A

immunotherapy targeted molecular therapies

stem cell transplantation

148
Q

sensory-discriminatory component of pain

A

how patient describes and experiences the pain

149
Q

motivational-affective component of pain

A

the psychology, mood of pain

depressive aspect of it, having had pain before

150
Q

cognitive-evaluative component of pain

A

what the pain means - good vs. bad pain (sore muscles vs. lung cancer)

151
Q

pain and depression

A

which came first? worsen each other - tightly linked impact pain and quality of life

152
Q

classifying pain

A

temporal

  • –acute
  • –chronic

etiology

  • –cancer
  • –non-malignant

pathophysiological

  • –nociceptive (visceral + somatic)
  • –neuropathic (peripheral + central)
153
Q

acute pain

A

patient appears in distress

temporally related to noxious stimuli

signs: increased BP, HR diaphoresis mydriasis pallor

154
Q

chronic pain

A

patient may not appear uncomfortable

pain extending beyond expected time course of syndrome

no obvious signs

care providers don’t want to give pain because patients don’t look like they’re in pain (adjustments)

155
Q

somatic pain

A

nociceptive originates from receptors in skin, bones, muscles, joints, blood vessels ull, aching, etc. and can point to where it hurts

156
Q

visceral pain

A

nociceptive when internal organs swell or become damaged within body

deep, gnawing, cramping and poorly localized

157
Q

nociceptive pain

A
  • process by which information about tissue damage is conveyed to CNS
  • direct stimulation of afferent nerves due to tissue injury or tumor infiltration of skin, soft tissue,
  • visceral pain is proportionate to stimulation of nociceptor
  • emotional component is anxiety or depression, the other sensory input, and the nociception itself
158
Q

nociceptive process

A
  1. peripheral tissues = transduction
  2. transmission to spinal cord to brain
  3. brain perception
  4. descending modulation to spinal cord
159
Q

pain transduction

A
  • nociceptor activation and sensitization
  • -nociceptors are free endings of primary afferent nerve fibers distributed throughout periphery
  • -noxious stimuli –> tissue damage -tissue damage –> chemical mediators
  • -action potential
160
Q

noxious stimuli

A

mechanical - touch/pressure

thermal - heat/cold

chemical - internal (help action potential generate) or external (ex: capsaicin)

161
Q

chemical mediators of tissue damage

A

bradykinin, K+, histamine, serotonin trigger release of prostaglandins, norepi, epi, and substance P

162
Q

fibers in pain transmission

A

A-alpha and A-beta fibers –> A-delta fibers –> C fibers

163
Q

A-alpha and A-beta fibers

A

fibers that we need in order to feel ‘

  • myelinated
  • large
  • proprioception, light touch
  • no thermal threshold
164
Q

A-delta fibers

A

transmit the first (ouch) pain

  • sharp, well-localized pain
  • mostly mechanical and thermal stimuli
  • myelinated
  • large diameter
  • rapidly conducting
165
Q

C fibers

A

the “reminder” pain

  • second pain (if it continues = chronic)
  • dull, aching, poorly localized pain
  • sensitive to mechanical, thermal, chemical stimuli
  • unmyelinated
  • small
  • slow
166
Q

pain transmission

A

fibers terminate in dorsal horn of spinal cord

release nt (Ca++ mediated) that bind NMDA receptors

signal terminates in thalamus (relay station to cortical regions)

167
Q

potential sites of pain modulation during transmission

A
  • -sodium to modulation action potential
  • -calcium-induced release of nt across synapse
  • -receptors for nt released by calcium
168
Q

pain perception

A

impulse becomes conscious experience of pain

169
Q

structures involved in pain perception

A
  • reticular system - autonomic response
  • somatosensory cortex - localization and characterization
  • limbic system - emotional and behavioral (harder to target with drugs - behavioral therapy)
170
Q

behavioral therapy for pain perception

A

distraction, relaxation, imagery

if patient believes it will work, it will work

171
Q

pain modulation

A

changing/inhibiting pain impulses

“rub it, it will feel better!”

172
Q

key players in pain modulation

A
  • endogenous opioids,
  • serotonin (5HT),
  • norepi (NE),
  • GABA
  • inhibit transmission of noxious stimuli
173
Q

rubbing a painful spot

A

activates non-nociceptive neurons which inhibit transmission of nociceptive info (A-beta fibers)

174
Q

endogenous opioids in pain modulation

A

block release of nts such as substance P

175
Q

NE and serotonin in pain modulation

A

increased by antidepressants to inhibit noxious stimuli

176
Q

GABA in pain modulation

A

increased by baclofen to reduce pain due to spasticity

177
Q

nociceptive process summary

A

transduction: noxious stimuli converted to impulses
transmission: movement of impulses up spine to brain
perception: recognizing, defining and responding to pain
modulation: descending pathways exert inhibition on pain transmission

178
Q

achieving zero pain

A

not always possible because we try to modulate natural pathways with drugs, which have adverse side effects

179
Q

inflammatory pain

A

adaptive mechanism that facilities healing of injured tissue (to avoid re-injury)

    • can be too much
  • abates and resolve with healing
  • increases sensitivity to stimuli in affected area
  • attributed to peripheral sensitization and central sensitization
180
Q

analgesia

A

reduced perception of pain stimuli

181
Q

anesthesia

A

reduced perception of all sensation

182
Q

paresthesia

A

abnormal sensation; not unpleasant

183
Q

dysesthesia

A

abnormal sensation; not pleasant

184
Q

allodynia

A

severe pain response to normally non-painful stimuli

185
Q

hyperalgesia

A

extreme response to painful stimuli

186
Q

secondary hyperalgesia

A

spread of sensitivity to noninjured areas

187
Q

peripheral sensitization

A

lower threshold for activation and increased rate of firing role in allodynia, hyperalgesia, central sensitization

chemical mediators saturate site of injury

188
Q

central sensitization

A
  • increased excitability of neurons w/in CNS
  • ongoing nociceptive input from periphery causes gradual increase in dorsal horn neuron firing (wind up)
  • prolongation of input results in longer-lasting dorsal horn excitability
  • causes changes in nerves that cause chronic pain
189
Q

“wind-up”

A
  • increase in NMDA receptors in dorsal horn that have an enhanced responsiveness to glutamate that causes impulses long after stimulus has ceased
  • NMDA receptors switch from low pain to high pain and perpetuates pain state
  • late phase is due to gene expression changes via activation of txn factors - long-lasting changes in dorsal horn neuronal fxn
190
Q

manifestations of central sensitization

A
  • hyperalgesia
  • allodynia
  • persistent pain (after stimulus ceases)
  • referred pain can persist
  • have injury heals in chronic pain states
191
Q

neuropathic pain

A
  • maladaptive
  • originates from direct neuronal injury resulting in disturbance of fxn or pathologic change
  • peripheral vs. central (where lesion occurs)
  • description: burning, stinging, numb, tingling, electric
192
Q

mechanisms of neuropathic pain

A
  • central sensitization
  • ectopic excitability
  • structural reorganization
193
Q

ectopic excitability in neuropathic pain

A
  • nerve regeneration results in sprouts and neuromas that fire spontaneously
  • peaks several weeks after injury
  • changes in Na/K channel expression
194
Q

structural reorganization in neuropathic pain

A

low-threshold sensory fibers terminate in areas where nociceptive neurons usually terminate - good things can feel like pain

allodynia and hyperalgesia

195
Q

examples of neuropathic pain

A

central: poststroke pain, MS, Parkinson’s, spinal cord injury (damage to CNS)
peripheral: postherpetic neuralgia, diabetic neuropathy, chemotherapy-induced neuropathy, HIV sensory neuropathy, phantom limb pain treated the same way

196
Q

consequences of pain

A
  • physiological
  • quality of life
  • financial
197
Q

physiological consequences of pain

A
  • acute pain that is not controlled
  • is more likely to become chronic than acute pain that is controlled
  • undertreated pain early in life is associated with pain later in life
198
Q

pain as 5th vital sign

A

led to a lot of opioid prescriptions - reeling it back while still treating it appropriately now

199
Q

nonpharmacologic treatment of pain

A
  • physical therapy
  • cognitive behavior therapy
  • stimulation therapy (TENS units)
  • cold/heat application
200
Q

pharmacologic treatment of pain

A

analgesics

adjuvants

201
Q

analgesic ladder

A

pain persisting or increasing –> pain persisting or increasing –> relief from pain

202
Q

step 1 in analgesic ladder

A

non-opioid

+/- adjuvant

203
Q

step 2 in analgesic ladder

A

opioid for mild/moderate pain

+/- non opioid

+/- adjuvant

204
Q

step 3 in analgesic ladder

A

opioid for moderate/severe pain

+/- non-opioid

+/- adjuvant

205
Q

Stage I symptoms of acetaminophen overdose

A

(12-14 hrs)

  • A/N/V
  • diaphoresis
  • pallor
206
Q

Stage II symptoms of acetaminophen overdose

A

(24-72 hrs)

  • RUQ abdominal pain
  • AST, ALT, lactate, phosphate,
  • bilirubin and PT/INR elevated
207
Q

Stage III symptoms of acetaminophen overdose

A

(72-96 hrs)

  • A/N
  • malaise
  • abdominal pain
  • confusion
  • liver failure
  • coagulation effects
  • encephalopathy
  • hypoglycemia
  • renal failure
  • cardiomyopathy
  • mortality w/o antidote: 3-4%
208
Q

opiates and opioids

A
  • from Greek word juice (opos)
  • 20 different naturally occurring alkaloids
  • opiates = naturally occurring products and semi-synthetic derivatives
  • opioids = all compounds related to opium
209
Q

MOA of opioids

A

decrease calcium presynaptically and increase K postsynaptically to slow/inhibit action potential

210
Q

Mu

A

in pain modulating regions of CNS

analgesia, euphoria, respiratory depression, miosis, reduce GI motility

211
Q

Kappa

A

in deep layers of cerebral cortex spinal

analgesia, sedation, miosis, respiratory depression, psychotomimetic and dysphoric effects

212
Q

Delta

A

in limbic regions of CNS spinal/paraspinal

analgesia, dysphoria, hallucinations, respiratory stimulation

213
Q

response to opioids

A

1st: analgesia
2nd: sedation
3: resp. depression

214
Q

tolerance

A

needing higher doses to elicit same response

215
Q

dependence

A

physiologic receptor response to exogenous substance and result from removing that substance

216
Q

addiction

A

any recurrent activity which results in negative consequences despite known consequence (includes social consequences)

217
Q

opioid induced hyperalgesia

A

increased pain despite increasing doses of opioids -confused with tolerance

218
Q

theories of opioid induced hyperalgesia

A
  • -toxicity of 3-position glucuronides (i.e. morphine)
  • -NMDA agonism
  • -increased spinal endogenous activity
  • -others
219
Q

antidepressants

A

block reuptake of nt, causing constant presence of nt

ex: serotonin, NE

220
Q

interventional anesthetics

A

epidural/spinal analgesia

nerve blocks

regional: anesthetize extremity but not entire leg

221
Q

capsaicin

A
  • depolarize nociceptors and release of substance P
  • decrease subs. P, decrease pain perception
  • decreased burning pain with regular use
  • must use 4x daily
  • always wash hands after
222
Q

drugs used in modulating central processing pathway

A
  • anticonvulsants
  • NMDA receptor antagonists
  • local anesthetics
  • antidepressants
  • opioids
223
Q

drugs used in modulating descending pathway

A

antidepressants

opioids

224
Q

drugs used in modulating ascending pathway

A

anticonvulsants

topicals NSAIDs

225
Q

most common infection sites

A

respiratory tract

urinary tract

226
Q

pneumonia

A

infection of lung tissue, from alveoli to interstitium with inflammation and impaired gas exchange

227
Q

UTI

A

microorganisms present in urinary tract not accounted for by contamination from vagina asymptomatic bacteriuria –> systemic infection complicated vs. uncomplicated

228
Q

pathogen

A

disease-causing microorganism

229
Q

infection

A

local shift in favor of pathogen over host with pathological consequences due to toxin production and invasion with subsequent inflammation

230
Q

endotoxins produced by…

A

gram negative

231
Q

exotoxins produced by…

A

gram positive

232
Q

virulence

A

strength of microorganisms’s pathogenicity factors include: adhesins and protective capsules

233
Q

adhesins

A

molecules that mediate adherence to cell surface

234
Q

inoculum

A

quanitity of microorganisms

235
Q

risk for infection

A

(inoculum x virulence)

host resistance

236
Q

atypical bacteria

A

won’t stain because their cell wall is thick, waxy, and hard

237
Q

gram positive stain

A

violet

238
Q

gram negative stain

A

pink

239
Q

infection: chain of transmission

A
  • reservoir
  • portal of exit
  • mode of transmission
  • portal of entry
  • susceptible victim
240
Q

possible reservoirs in chain of transmission

A

human

animal

insect

soil

241
Q

possible portals of exit in chain of transmission

A

nasal mucosa

oral mucosa

242
Q

possible modes of transmission

A

insect bite

nasal droplets

semen

243
Q

possible portals of entry in chain of transmission

A

nasal mucosa

oral mucosa

skin abrasion

skin puncture

244
Q

possible susceptible victims in chain of transmission

A

malnourished

unimmunized

immune compromised

245
Q

incubation

A

time between exposure and symptoms

246
Q

prodrome

A

non-specific symptoms often a feeling of malaise, may have headache, fatigue, other non-specific symptoms

247
Q

illness

A

over S/Sx of infection

248
Q

recovery

A

return toward homeostasis

249
Q

chronic carrier state

A

possible in some infections

250
Q

CAP

A

community acquired pneumonia

251
Q

HAP

A

hospital-acquired pneumonia: diagnosis made >48 hr after admission

252
Q

VAP

A

ventilator-associated pneumonia: diagnosis made 48-72 hr after endotracheal intubation

253
Q

HCAP

A

healthcare-associated pneumonia: diagnosis made

254
Q

healthcare-associated pneumonia risk ractors

A
  • -hospitalized in acute care hospital >48 hr within 90d of diagnosis
  • -resided in nursing home/long-term care facility
  • -received recent IV antibiotic therapy, chemo, wound care w.in 30 days before diagnosis
  • -attended hospital/hemodialysis clinic
255
Q

VRSA

A

vancomycin-resistant staphylococcus aureus

256
Q

MDR

A

multi-drug resistant

257
Q

risk factors for pneumonia

A
  • 65 yo
  • smoker
  • lung disease
  • chronic disease (DM)
  • hospitalization
  • immobility
  • depressed cough reflex
  • dysphagia
  • immunocompromised
  • flu
  • alcoholism
  • IV drug abusers
  • malnourishment
  • inhalation of chemicals
258
Q

mucociliary escalator

A

respiratory tract defense mechanisms

80% cells lining central airways are ciliated, pseudostratified, columnar

each has 200 cilia that beat 1000x/min

any bacteria/particle > 5um trapped in mucus and exit via mucociliary escalator up the throat and eliminated via cough reflex or swallowed (acid)

259
Q

alveolar macrophages

A

always present and can phagocytose bacterial invaders 5 um that make it into the lungs

release inflammatory cytokines to recruit other cells of inflammation

complement, IgA, IgG, T cells play roles

260
Q

virulence of S. pneumoniae

A
  • external polysaccharide capsule to avoid phagocytosis
  • secretes protein to adhere to mucosa in upper airways
  • secretes protein to destroy ciliated cells
  • secretes protease to inhibit IgA (which normally binds bacteria to mucus to facilitate clearance)
261
Q

bacteria make it to the lungs via

A

inhalation (most common)

aspiration

hematogenous (bloodstream, least common)

262
Q

inflammatory response r/t pneumonia

A

started by alveolar macrophages

    • Il-6 and TNF-a initiate fever
  • -other cytokines attract neutrophils which kill bacteria via ROS, enzymes, antimicrobial proteins (cause damage to lung tissue)
  • -neutrophils extrude meshwork with antimicrobial proteins to trap and kill bacteria (neutrophil extracellular traps - NETS)
  • -inflammatory mediators released/recruited by macrophages create alveolar capillary leak
  • -alveolar spaces fill with exudative fluid and debris
263
Q

S/Sx of pneumonia

A
  • fever chills
  • dyspnea
  • productive cough
  • pleuritic chest pain
264
Q

physical exam results of pneumonia

A

tachypnea, tachycardia, dullness to percussion, diminished breath sounds, inspiratory crackles, tactile femitus, egophony

265
Q

other clinical manifestations of pneumonia

A
  • infiltrate on CXR
  • proper specimen, gram stain, culture &
  • susceptibility
  • leukocytosis with PMNs predominating,
  • low O2 sat
266
Q

PMN

A

polymorphonuclear cells, aka granulocytes, of which neutrophils are most dominant type

267
Q

extra-pulmonary clinical manifestations of pneumonia

A
  • bradycardia
  • abdominal pain
  • myalgias
  • others
  • most common in atypical pathogens
268
Q

CURB-65 criteria

A

determines inpatient or outpatient treatment 1

pt each for:

C - Confusion

U - Uremia; BUN > 20

R - Respiratory rate > 30 B - low BP; SBP

65 yo

269
Q

CURB-65 scoring

A

0 = low, outpatient

1 = low, outpatient

2 = moderate, outpatient (supervised) or inpatient (short)

3 = mod-high, inpatient

4/5 = high, inpatient (ICU)

270
Q

cystitis

A

lower UTI infection of bladder and/or urethra

271
Q

pyelonephritis

A

upper UTI infection

above bladder; kidneys, ureters, peri-renal tissue

may result from bladder bacteria ascending into ureters and kidneys

272
Q

complicated UTI

A

(upper or lower): associated with underlying condition that increases risk of therapy failure

273
Q

underlying conditions of complicated UTI

A
  • diabetes
  • pregnancy
  • S/Sx > 7 days w/o care
  • hospital acquired infection
  • renal failure
  • urinary tract obstruction
  • indwelling catheter, etc.
  • recent urinary tract instrumentation
  • fxnal/anatomic abnormality of UT
  • UTI history in childhood
  • renal transplantation
  • immunosuppression
274
Q

uncomplicated UTI

A

upper or lower healthy nonpregnant adults w/ no risk factors for treatment failure

275
Q

risk factors for UTI

A
  • structural abnormality in UT (VUR and BPH)
  • urinary stasis
  • female anatomy (#1 risk factor)
  • improper hygiene
  • postmenopausal
  • prior UTI
  • recent sexual activity
  • spermicides, diaphragms
  • DM, CKD
  • catheterization/indwelling catheters
  • pregnancy
  • other instrumentation in UT
276
Q

VUR

A

vesicoureteral reflux

condition where urine reflexes back upwards

277
Q

BPH

A

benign prostatic hyperplasia

278
Q

normal defense mechanisms of urinary tract

A

-urine flushes out bacteria before they can adhere to bladder wall -low pH of urine; intolerable to most bacteria -proteins secreted by kidney prevent bacterial adherence -vaginal lactobacilli kill uropathogens -mucopolysaccharide lining of urethra/bladder inhibits penetration and adherence of bacteria -prostatic secretions are bactericidal -secretory IgA -infalmmatory response

279
Q

why is E. coli such a common cause of UTI?

A

-large quantities in gut; proximity to vagina and urethra -flagellae permit mobility -virulence factors -surface adhesions that mediate binding to receptors on uroepithelial cells in urethra/bladder -fimbriae permit adherence fo uroepithelial cells and block phagocytosis -polysaccharide capsule -hemolysin induces formation of pores in cell membrane of epithelial cells, RBCs, immune cells -iron transport system to uptake iron in iron-poor environments

280
Q

pathophysiology of UTI

A

urinary tract usually sterile -bacteria establish infection in most UTIs via ascension from urethra to bladder (colonization of vaginal introitus and periurethral area with gut microorganisms) hematogenous spread more rare, usually to kidneys bacteria adhere to urethra/bladder epithelium and invade/multiply - form biofilm toxins secreted by bacteria damage epithelium - exfoliation of epithelium inflammatory response continuing ascent is pathway for pyelonephritis

281
Q

clinical manifestations of lower UTI

A
  • dysuria
  • urgency
  • frequency
  • nocturia
  • suprabuic heaviness/pain
  • gross hematuria
  • bacteriuria, pyuria
  • nitrite (+), leukocyte esterase (+)
282
Q

clinical manifestations of upper UTI

A
  • fever, chills
  • flank pain
  • N/V
  • malaise
  • costovertebral tenderness (CVA)
  • bacteriuria, pyuria nitrite (+), leukocyte esterase (+)
  • antibody-coated bacteria
283
Q

clinical manifestations of pneumonia and UTI in geriatric patients

A

may not present with classic symptoms (may not be febrile) common cluster of symptoms in both is “change in mental status”:

  • -confusion
  • -delirium (may be misdiagnosed as or superimposed on dementia)
  • -lethargy
  • -sudden incontinence (esp. in UTI)
284
Q

bacteremia

A

bacteria in bloodstream

285
Q

SIRS definition

A

systemic inflammatory response syndrome

infectious or non-infectious

286
Q

sepsis

A

SIRS due to infectious causes

287
Q

severe sepsis

A

sepsis with 1+ organ dysfxns, hypoperfusion, or hypotension

288
Q

septic shock

A

sepsis w/ persistent hypotension despite fluid resuscitation, along w. perfusion abnormalities

289
Q

SIRS symptoms

A

2+ of:

  • -core temp >38.3C or 90bpm -RR>20 or PaCO2 12,000 or 10%
  • -cardiac index > 3.5 L/ min*m^2
  • -plasma CRP or procalcitonin > 2 std dev above normal
  • -altered mental status
  • -arterial hypoxemia, hyperlactatemia, decreased cap refill, coagulation abnormalities
  • -acute oliguria, increased creatinine, positive fluid balance
  • -thrombocytopenia
  • -ileus, hyperbilirubinemia
  • -hyperglycemia
290
Q

prophylactic therapy for infection

A

preventative requires knowledge of the most likely pathogens -

for individuals at risk for infection make best choice of antimicrobial that will reduce pathogen at potential site of infection

291
Q

empiric therapy for infection

A

what the bacteria is likely to be make best choice of antimicrobial that will help eradicate the pathogen at site of infection;

take host factors into account

292
Q

definitive therapy

A

data on pathogen(s) and susceptibility pattern(s) to antimicrobials is already known

narrow (de-escalate) from initial empircal therapy

293
Q

disk-diffusion

A

qualitative method to measure pathogen susceptibility

disk infused w. antibiotic is placed on agar plate

294
Q

minimum inhibitory concentration (MIC)

A

drug concentration at which organism’s growth is inhibited

295
Q

minimum bactericidal concentration (MBC)

A

drug concentration at which organism death occurs

296
Q

susceptibility determined by

A

MIC values (+)

clinically achievable drug concentrations at site of infection

297
Q

ideal antimicrobial propeties

A
  • selective toxicity
  • easily classified
  • no acquired resistance
298
Q

selective toxicity

A

gets the bug and not the host

gets the right bug with no collateral damage to microbiota of gut, GU tract, etc.

299
Q

antimicrobials: easily classified based on

A
  • organism
  • susceptibility
  • mechanism of action
300
Q

no acquired resistance

A

keep organism susceptibility from evolving

organism susceptibility changes over time

301
Q

superinfection

A

a new infection that appears during treatment of a primary infection

develops when antibiotics kill microbiota that normally inhibit pathogenic

bacteria more likely to occur with broad spectrum Abx

302
Q

C. difficile superinfection - etiology

A

G+, spore-forming, anaerobic bacillus that infects bowel injury to bowel

caused by release of toxins - causes intense, frequent diarrhea (dehydration and electrolyte imbalance)

303
Q

C. difficile superinfection - development

A

almost always preceded by antibiotic use

  • -spore ingested or may already be present, but under control
  • spores transferred to patient via hands of healthcare workers
  • -spores remain viable in environment for weeks
  • -once ingested, spores enter vegetative state and reproduce
  • -spores can go thru stomach acid
304
Q

C. difficile superinfection - elimination

A

offending antibiotic stopped and other antibiotic started to kill C. diff can be difficult to eradicate and can recur

contraindicated with drugs that slow bowel motility - increased toxicity from C. diff toxins

305
Q

resistance to antibiotics

A

biggest current challenge to effective treatment of infectious diseases

306
Q

natural resistance

A

organism has an inherent train that makes it resistant to the drug

ex:

  • -absent drug target molecule or process
  • -altered cell surface permeability to drug
307
Q

acquired resistance

A

ex:

  • -enzymes that modify/inactivate drug
  • -altered ability to accumulate drug (efflux)
  • -modified site of action for drug
  • -altered cell surface permeability to drug
308
Q

how does acquired resistance occur?

A

spontaneous mutations

    • rapid growth rate and large number of cells
  • -resistance genes transferred directly to all bacteria’s progeny during DNA replication
  • cell-cell contact: direct transfer of plasmids taken up from external environment after death/lysis of another bacterium
  • bacteria-specific viruses (bacteriophages) that transfer DNA between two closely related bacteria
309
Q

beta-lactam ring

A

integral part of many antibiotics susceptible to B-lactamase, which cleaves ring and renders drug inactive

resistance bacteria produce variety of B-lactamases

310
Q

generalized MOAs of antibacterial agents

A
  1. cell wall active
  2. interfere w/ protein synthesis
  3. interfere with nucleic acids
  4. anti-metabolite antibacterials
311
Q

bacterial cell wall : gram+ vs. gram-

A

G+: thicker peptidoglycan layers, but simpler structure. penicillin easily penetrates

G-: thinner peptidoglycan layer but more complex walls. outer membrane with pores to restrict entry, plus lipopolysaccharide for integrity purposes and to protect membrane from chemical attack. only some penicillins can cross outer membrane both have penicillin-binding proteins (PBP)

312
Q

PBP

A

penicillin-binding proteins

penicillin must bind to them to produce antibacterial effects

313
Q

transpeptidase

A

penicillin-binding protein that normally creates crossbridges between strands of peptidoglycan polymers to give the cell wall added strength

by inhibiting them, penicillins prevent crossbridge formation and weaken cell wall

314
Q

MRSA

A
  • methicillin-resistant staphylococcus aureus
  • acquired genes that code for PBPs with low affinity for penicillins and cephalosporins, so they cannot exert antibacterial effects
  • resistant to all penicillins and cephalosporins
  • initially only in healthcare environments; community MRSA now common

causes skin and soft tissue infections:

  • -furuncles and carbuncles
  • -necrotizing fasciitis
  • -pneumonia

spreads via skin-skin contact

315
Q

aminoglycoside MOA

A

bind to 30S ribosomal subunit and

1) block initiation
2) terminate synthesis early
3) cause misreading of genetic code

316
Q

fluoroquinolone MOA

A

interrupt DNA replication and txn by inhibiting bacterial topoisomerase IV (DNA unwinding) and DNA gyrase (DNA supercoiling)

317
Q

sulfonamide MOA

A

disrupt bacterial folic acid synthesis (necessary step in nucleotide synthesis)

318
Q

bacteriostatic antibiotics

A

prevent bacterial growth

319
Q

bactericidal antibiotics

A

kill bacteria outright

320
Q

concentration-dependent antibiotics

A

as the concentration of the drug increases, the rate and extent of bacterial killing increases

321
Q

time-dependent antibiotics

A

the duration of exposure to drug ABOVE THE MIC is key.

beyond a certain point, increasing concentration does not increase rate of bacterial killing

322
Q

dosing a concentration-dependent antibiotic

A

once/day dosing has same effectiveness as 3x/day dosing but once/day means more of the 24hr period is under MIC and minimizes development of adverse rxns such as ototoxicity

323
Q

dosing schemes

A

allow best chance for drug to get bug

combining antibiotics occasionally

  • -prevent resistance
  • -polymicrobial infection
  • -synergy
324
Q

penicillin allergy

A

most common cause of drug allergy

severity: minor rash to life-threatening anaphylaxis

GI upset is not an allergic rxn

325
Q

differentiating cephalosporins

A

newer generations more active against G- bacteria and less susceptibility to B-lactamase enzyme

3rd and 4th only ones that can treat brain infections (CSF)

326
Q

patient teaching to reduce development of antibiotic-resistant bacteria

A
  • finish entire course
  • do not borrow others’ antibiotics
  • colds/URIs are viral, not bacterial
327
Q

antibiotic side effects

A

any antibiotic can cause GI upset (N and V/noV)

many antibiotics can cause candidiasis

these are NOT allergic rxns

328
Q

administering antibiotics

A
  • many will be IV
  • always check allergies
  • always check infusion time - can cause rxn if too quick
  • an allergy can develop at any time
  • stop infusion FIRST if you observe an allergy, then proceed with additional interventions

Pathophysiology, Pharmacology, and Therapeutics (7 decks)

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