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FOM Final Review > Week 4 > Flashcards

Week 4 Flashcards

0
Q

Talk about Rifampin

A
  • Inhibits RNA Polymerase
  • Bactericidal
  • Used to treat TB (RIPES)
  • Binds to bact. RNA Polymerase at active center, preventing elongation of the mRNA
  • Causes GI side effects, turns fluids orange-red & stains contact lenses, can induce cytochrome p450 enzyme CYP3A4 which can induce metabolism of other medicines [leads to organ rejection and loss of seizure control]

Acquired Resist= strain acquires mutations in rpoB gene
Intrinsic Resist= drug is unable to bind beta-subunit of RNA polymerase

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1
Q

What are the two inhibitors of RNA Polymerase?

A

Rifampin and Fidoxamicin

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2
Q

Talk about Fidoxamicin

A
  • Bactericidal
  • Inhibits Bact. DNA Polymerase
  • Narrow spectrum: gram + bacteria, anaerobic bacteria, especially C, difficle [spares gut flora]
  • low absorption = few side effects
  • Some bacteria are resistant due to a point mutation in RNA Polymerase
  • New drug, only available for the past year
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3
Q

What three Fluoroquinolones do you need to know?

A

Levofloxacin, Ciprofloxacin, Moxifloxacin

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4
Q

Tell me about Fluoroquinolone potency, spectrum and mechanism:

A
  • Bactericidal
  • Very Broad Spectrum - Gram + and Gram -, along with atypical organisms (Mycoplasma)
  • Frequently used for pneumonia & UTI
  • Mech: Inhibits DNA replication (binary fission in bacteria) by binding bacterial DNA Topoisomerase II (gyrase) & IV
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5
Q

What is the different effects induced by Fluoroquinolones on Gram - and Gram + organisms?

A

Gram -: Inhibits Topoisomerase II (DNA gyrase) and prevents relaxation of pos. supercoiled DNA required for normal transcription and replication

Gram +: Inhibits Topoisomerase IV - interferes with the seperation of replicated chromosomal DNA (decatenation) into the daughter cells during cell division

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6
Q

What side effects can Fluoroquinolones induce?

A

GI side effects, Confusion, Photosensitivity, Inc. in C. difficle colitis, Inc. in candida vaginitis, tendon problems/joint disease in pregnant women, breastfeeding women and children
–Patients are supposed to avoid dairy & Calcium (Ca, Fe, Al, Zn) = drug has chelate cations

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7
Q

What resistance has developed against Fluoroquinolones?

A
  • They have been overprescribed for UTI, resp. infections & acute GI infections –> causes resistance
  • Resist: Active efflux of the drug, mutations in topoisomerase, activation of DNA stress response (SOS) & DNA repair - repair of dsDNA breaks
  • Some bacteria upregulate many transporters that can efflux many different drugs = multidrug resistance!
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8
Q

What is unique about Ciprofloxacin?

A

Fluoroquinolone

-used to treat & prevent dangerous illnesses deliberately spread (ex: plague, tularemia & anthrax of skin or mouth)

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9
Q

What are the folate agonists?

A

Sulfonamides & Trimethoprim
Mech: Work by indirect inhibition of DNA synthesis
Spectrum: Bacteria & fungi that synthesize their own dihydrofolic acid

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10
Q

Tell me about Trimethoprim.

A

-Bacteriostatic
Mech: Inhibits bacterial dihydrofolate reductase (drug has dec. affinity for mammalian version of the enzyme)
Side effect: GI upset
Resistance: Altered dihydrofolate reductase, Inc. amouts of dihydrofolate reductase & alternative metabolic pathways

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11
Q

Tell me about Sulfamethoxazole.

A

-Bacteriostatic
Mech: Para aminobenzoic acid (PARA) analog & acts as competitive inhibitor of dihydropteroate synthetase
Resist: Through change in dihydropepteroate synthetase (first enzyme in folate synthesis pathway) which causes an increase in efflux of the drug & increase in production of PABA
Side Effects: Hypersensitivity, Steven-Johnson syndrome, cross reaction with drugs, Crystalluria –> renal failure, hemolysis & kerniterus

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12
Q

TMP-SMX

A

Also called Bacitrin
Combination of 2 drugs that sequentially block the folate synthesis pathway
-bactericidal together
Spectrum: broad UTI treatment & pneumocystis
–People with sulfa allergies use TMP alone
–If patient has a glucose 6-phosphate dehydrogenase deficiency, they should not be given SMX!!! – So treat their UTI with Nitrofurantoin/

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13
Q

How do sulfonamides cause Kernicterus?

A

Kernicterus = neurological condition that occurs in severely jaundiced newborns
–SMX compete for binding to albumin leading to free bilirubin & complications with drugs like warfarin –> this leads to kernicterus due to a build up of bilirubin in the pathway

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14
Q

Tell me about Metronidazole.

A

Bactericidal
Targets: C. difficle & protozoans (anaerobes)
Mech: Indirect inhibitor of DNA, when reduced & active it will generate free radicals leading to DNA strand breaks and cell death
Drug resist: Rare
Side effects: nausea, diarrhea, headache & metallic taste
-Avoid during pregnancy & avoid alcohol use [drug undergoes a disulfram like reaction]
-Only metabolized into its active form in anaerobes

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15
Q

Tell me about Nitrofurantoin.

A

Bactericidal
-Broad spectrum
Mech: Bact. flavoproteins reduce it to reactive intermediates that inactivate bacterial ribosome proteins –> inhibit synthesis of DNA, RNA, cell wall & proteins
Side effects: Vomiting & Rash
–Bacteria hasn’t yet developed resistance

It’s rapidly excreted in the urine in its active form so its only good for UTI infections!!

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16
Q

Tell me about Linezolid.

A

Oxazolidinone
-Bacteriostatic
Targets: gram (+), MRSA, Vanco. resistant Enterococci
Mech: Inhibits protein synthesis by binding 23s ribosomal RNA on the 50s subunit & preventing formation of the intiation complex [binds to P site on the 50s]
Side effects: Bone marrow suppression, serotonin syndrome [if taken with SSRI]
Resist: Alterations of modifications in 23S ribosomal RNA

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17
Q

What are the aminoglycosides?

A

Gentamicin, Amikacin, Tobramycin, Neomycin, Streptomycin

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18
Q

Aminoglycoside: Spectrum, Mech, Class, Admin.

A

Bactericidal

  • Target: gram (-) aerobic, usually used in combination with other drugs
  • Mech: prevents formation of the initiation complex, causes mRNA misreading, induces early termination
  • Admin: poor gut adsorption, usually given IV, polar drug, excluded from CSF
  • ->requires energy to enter the cell
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19
Q

Aminoglycosides: Side effects, Resistance

A

Side effects: Tubular necrosis: 1)nephrotoxicity 2)Ototoxicity (vestibular and auditory disfunction) 3) Pregnancy Class D -hearing loss in fetus
Resistance: Intrinsic: failure of drug to enter bact. cell - cotreat with cell wall inhibitor
Acquired: acquisition of enzymes that inactivate the drug through acetylation, phosphorylation or adenylation

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20
Q

What’s unique about the aminoglycoside Amikacin?

A

It’s broader spectrum [including pseudomonas] & less susceptible to enzyme inactivation

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21
Q

What are the four tetracyclines you need to know?

A

Tetracycline, Doxycycline, Minocycline, Demeclocycline

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22
Q

Tetracycline: Mech, Spectrum, Resistance

A

Mech: Bind to the 30s subunit, prevent attachment of amino-acyl-tRNA
Spectrum: Broad initially but now resist: H. burgdorferi, H. pylori, Mycoplasma pneumoniae
Resist: Intrinsic: decreased uptake
Acquired: Increased efflux and alteration of ribosomal target [rarely enzymatic inactivation]

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23
Q

Tetracyclines: Side effects

A
  • Form stable chelates with metal ions (Ca, Mg, Fe, Al- decreases the gut absorption of the drug]
  • GI irritation & photosensitivity (abnormal sunburn)
  • teeth discoloration
  • inhibits bone growth in children (sometimes)
  • pregnancy class D
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24
Q

Chloramphenicol

A

Bacteriostatic
Spectrum: Extended but use is limited due to severe side effects
Mech: Binds 50s subunit, preventing peptide bond formation- peptidyltransferase can’t associated with the amino acid substrate
Resist: Acetyltransferase modifies drug target to prevent binding to ribosome
SE: TOXIC - bone marrow depression & aplastic anemia (bone marrow doesn’t make new RBCs), Gray baby syndrome- don’t use in pregnancy

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25
Q

What is gray baby syndrome?

A

Premature infants lack the enzyme UDP-glucuronyl transferase and have low renal function so high levels of the drug accumulate which can lead to cardiovascular and respiratory collapse

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26
Q

What are the Macrolides?

A

Erythromycin, Azithromycin & Clarithromycin

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27
Q

Tell me about Macrolides.

A

Bacteriostatic
Target: broad coverage of resp. pathogen - Chlamydia
Mech: Inhibits translocation by binding 23s rRNA of the 50s subunit, prolonged QT interval, inhibitors of cytochrome p450
Resist: Methylation of 23s rRNA binding site, increased efflux, hydrolysis of macrolide by esterases
Clarithromycin– not safe for pregnancy!!

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28
Q

Tell me about Clindamycin.

A

It’s a Lincosamide (class)
Bacteriostatic
Targets: gram(+), including anaerobic, treat acne
Mech: blocks translocation at 50s ribosomal subunit
Side effects: hypersensitivity (rash, fever), diarrhea, abdominal pain, mucus & blood in stool, super-infection with C. difficle
Resist: Mutation in ribosome, methylation of ribosomeal RNA, cross-resistant with macrolides & streptogramins, inactivation of drug by adenylation

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29
Q

Tell me about Quinupristin/Dalfopristin.

A

Class: Streptogramins
Bactericidal - for some organisms when combined
Targets: should be solved for infections caused by multiple drug resist. G (+) bacteria
Mech: Inhibits translocation by binding 50s subunit
SE: High incidence including arthralgias & myalgias are common, inhibits p450 & likely to have sign. drug interactions
Resist: Ribosomal methylase prevents binding of drug to target, enzymes inactivate drugs, efflux proteins pump drug out of the cell, X-resistance with Macrolides & Clindamycin

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30
Q

What’s unique about Mycoplasma pneumonia?

A

It’s an atypical pneumonia, beta-lactams are not effective against it.
-Can use: Doxycycline, Azithromycin, Levofloxacin

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31
Q

What agents may cause hemolysis in patients with glucose 6-phosphate dehydrogenase deficiency?

A

Sulfonamides (Trimethoprim/Sulfamethoxazole)

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32
Q

Css

A

Steady State Concentration

Kin (drug input) /Cl (drug clearance)

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33
Q

Vd

A

Volume of distribution

Total drug/C0 (plasma concentration of the drug)

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34
Q

t(1/2)

A

half life

0.693(Vd/Cl)

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35
Q

ke

A

Elimination Constant

Cl (drug clearance)/Vd (volume of distribution)

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36
Q

Loading Dose

A

(CssXVd)/f

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37
Q

Maintenance Dose

A

[Dosing rate (unit/time) that acheives desired level of effect X Dosing interval (hrs)]/f (bioavailability)

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38
Q

What are the basics of alcohol metabolism?

A

Ethanol – (ADH/ADH2 or MEOS) –> acetaldehyde – (ALDH/ALDH2) -> acetate - (acetyl CoA synthetase - ACS) –> Acetyl CoA –> liver (FA synthesis) or muscle (TCA cycle)

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39
Q

Treatment of E. coli UTI (75-95% of cases)

A
  • Many bacteria have gained resistance to TMP-SMX and Fluoroquinolones, but this is variable by community
  • Many enterobacteeriaceae have acquired plasmids expressing extended-spectrum Beta-lactamases
  • Nitrofurantoin is preferred in cases of resistance
40
Q

Minimum Inhibitory Concentration (MIC)

A

Minimum concentration at which the drug can inhibit growth

41
Q

Mechanistic View

A

Describes how events happen (cause and effect), Sequence of events

42
Q

Teleologic Approach

A

Explains why events happen and explains the purpose of an event starting with the end of the story

43
Q

Where does filtration and readsorption happen in the Kidneys?

A

Filtration of fluid and electrolytes happens in the glomerulus and readsorption happens in the tubules/rest of nephron

44
Q

Explain respiration in the context of partial pressures:

A

Partial pressure of O2 is high in the lungs and low in the bloodstream so O2 flows into the blood. Partial pressure of CO2 is low in the lungs and high in the bloodstream which means CO2 flows into the lungs. When PCO2 is high and PO2 is low, ventilation increases.

45
Q

Circulatory Flow =

A

cardiac output from heart pump = stroke volume [total volume you’re processing] X heart rate [how often you’re contracting]

46
Q

Function of the Spleen

A

Removes old red blood cells and bacteria [removes opsinized/antibody covered cells]

47
Q

What does the Na+K+ ATPase do?

A

It establishes a concentration gradient (about -12 mV) which ion channels then use. It pumps 2K+ into the cell and 3Na+ out of the cell.

48
Q

What happens if hydrostatic (outward) pressure in the blood vessel is greater than osmotic (inward) pressure?

A

Net filtration

If hydrostatic is lower than osmotic, you get net adsorption

49
Q

Flow =

Where does blood flow more slowly?

A

Pressure/Resistance
Blood flows more slowly near the vessel wall due to higher resistance. Dilating your blood vessels reduces resistance to increase flow.

50
Q

What is the difference between the somatic and autonomic nervous system?

A

The somatic nervous system is voluntary and controls skeletal muscle contractions. Meanwhile, the autonomic nervous system is involuntary and provides automatic regulation of smooth muscle. The autonomic system has two branches: (1) sympathetic (fight or flight) and (2) parasympathetic (rest & digest)

51
Q

EGFR

A

Thought to be a good target for cancer drugs since it’s a receptor present on all cancer cells. Patients must have their tumor sequenced before we can determine if they can be give such an expensive drug

52
Q

How does grapefruit juice influence the cytochrome p450?

A

It can reduce 3A4 to a toxic amount. This induces a state similar to ultra rapid metabolism (high 2D6 and low 3A4)

53
Q

What does quinidine do to cytochrome p450?

A

Quinidine is a medication that corrects disturbances in heart rhythm and is used to treat malaria. It reduces 2D6, inhibiting codeine metabolism - high 3A4 and low 2D6- mimics poor metabolism

54
Q

Extensive Metabolizers

A

Normal - feel pain relief - have a little more 2D6 than 3A4

55
Q

Poor Metabolizers

A

More 3A4 than 2D6 - Metabolism blocked, patient may OD on less drug

56
Q

Ultrarapid metabolizers

A

Metabolizes too quickly to benefit - 2X more 2D6 than 3A4 - No pain relief

57
Q

General Ideas about Metabolism

A

If 2D6 Increases = Metabolism Increases

58
Q

Cytochrome p450

A

This gene family contributes to the metabolism of over half of all medications. Cytochrome p450 3A4 (CYP3A4) is expressed in the liver and intestines. It is an essential enzyme involved in detoxification.

59
Q

Direct Sequencing

A

Most common method of detecting SNPs and is very accurate if you find the change that you’re looking for. The only problem is sifting through all of the data that the test outputs.

60
Q

Deep Sequencing

A

With deep sequencing, usually 20 genes are taken out and analyzed out of all the genes in the genome. With deep sequencing, you have DNA & RNA from the patient and you want to know every change/piece of RNA/DNA in the genes.

61
Q

What are methods used to detect genetic variants (SNPs - Single nucleotide polymorphisms - not always a mutation/bad)?

A

Deep sequencing, Exon Trapping and Direct Sequencing

62
Q

What is a polymorphism?

A

A naturally occurring variation in the DNA (base pair sequence). The encoding protein’s function may or may not be altered.

63
Q

Vitamin K

A

Natural blood clotting factor that can reverse the blood thinning effects of warfarin

64
Q

Pharmacokinetics

A

How body acts on drug

65
Q

Pharmacodynamics

A

How drug acts on body

66
Q

What things increase the effect of warfarin?

A

VKORC1 Polymorphism (mutation - dec. vita K), CYP2C9 Polymorphism (*2 *3 mutations - dec. metabolism), Aspirin (antiplatelet), Glipizide (substrate for 2C9 - dec. metabolism), Cimetidine (inhibits 2C9 - dec. metabolism)

67
Q

What things decrease the effect of warfarin?

A

Antacids (dec. adsorption), Rifampin (Inducer of 2C9 - Inc. metabolism)

68
Q

What unique thing can increase or decrease warfarin’s effect depending on it’s presence?

A

Vitamin K/Salads - Vitamin K blocks warfarin’s binding spot so it works less well if you eat a lot of salad

69
Q

What is the effect of Vitamin K on warfarin?

A

It causes coagulation so it combats the effects of warfarin.

70
Q

What drugs are used most often for C. difficle infections?

A
  1. Metronidazole
  2. Fidoxamicin (relatively new)
  3. Vancomycin
73
Q

What is a physiological antagonist?

A

It involves interactions between regulatory pathways mediated by different receptors [Ex: insulin vs. glucocorticoids] - doesn’t involve binding to a receptor but it involves opposing effects/pathways

74
Q

Median lethal dose (LD50)

A

Dose that produces death in 50% of the population

75
Q

What is the therapeutic index (TI)?

A

A measure of relative safety determined by the ratio of LD50 (how much drug it takes to kill half the population) over ED50 (how much drug it takes for half the population to respond) - As TI increases, toxicity decreases

76
Q

What does ADME stand for?

A

Absorption
Distribution
Metabolism
Excretion

77
Q

Kidneys -

Liver -

A

Major organ for excretion

Major organ for metabolism

78
Q

How does the effect of pH on diffusion lead to iron trapping?

A

In very basic (high pH), a weak acid will be trapped (NaHCO3) and therefore eliminated in the kidneys.
In very acidic (low pH) a weak base will be trapped (bicarb) and therefore eliminated in the kidneys.

79
Q

What does first-pass metabolism mean?

A

A drug is transformed when it passes through the liver and has no effect orally

80
Q

What happens to the Vd of an obese patient?

A

Obese patients usually have a lower water content than the average person and higher adipose tissue content. This means that if drug is neutral hydrophobic/lipophilic, it will aggregate in the adipose tissue which will make the Vd of an overweight person larger than a lean and fit patient.

81
Q

What determines the composition of urine?

A

Glomerular filtration, reabsorption, and secretion

82
Q

What happens in glomerular filtration?

A

The glomerulus is a cup-shaped capillary bed at the head end of the renal tubule. The plasma filtrate formed at this point becomes pre-urine. Only free, unbound drug or metabolite in plasma is filtered.

83
Q

What happens in reabsorption in the kidney?

A

Includes both facilitated transport and passive diffusion. Acidification of urine increases the excretion of weak acids and alkalization of urine increases excretion of weak acids

84
Q

What is the function of secretion (in kidney)?

A

Active transport processes for acids and bases

85
Q

What three major factors affect the internal distribution of a drug?

A
  1. Relative tissue perfusion rates
  2. Plasma protein binding
  3. Partitioning between plasma and tissues
86
Q

What does plasma protein binding mean?

A

It means that bound drugs do not cross membranes are a pharmacologically inert. The free conc. of drug is reduced which reduces the gradient responsible for passive diffusion. [Ex: albumin which binds many weak acids]

87
Q

What is plasma partitioning?

A

It involves pH and ion trapping of different concentrations of the drug in each compartment, tissue protein binding (drug binds and gets stuck to tissue) and lipid solubility (drug binds to adipose tissue and becomes inactive)

88
Q

What are the 30s inhibitors?

A

Aminoglycosides & tetracycline

89
Q

What are the 50S inhibitors?

A

Linezolid, Macrolides, Chloramphenicol, Clindamycin, Quinupristin/Dalfopristin

90
Q

What drugs act at translation initiation?

A
  1. Linezolid binds to the P site on the 50s

2. Aminglycosides bind to the 30s ribosome and freeze the initiation complex

91
Q

What six drug sets work during elongation of translation?

A
  1. Aminoglycosides
  2. Tetracycline - prevent aminoacyl tRNA attachment to the acceptor site
  3. Macrolide - inhibits translocation from A to P
  4. Chloramphenicol - inhibits peptide bond formation
  5. Clindamycin - inhibits translocation from A to P
  6. Quinopristin/Dalfopristin - inhibits translocation from A to P
92
Q

What antibiotics work at translation termination?

A

Aminoglycosides

93
Q

Tell me about concentration dependent killing:

A
  • Achieve more killing at higher concentration
  • Peak conc. much higher than MIC
  • -Aminoglycosides and Fluoroquinolones
94
Q

Tell me about Time-dependent killing:

A

t>MIC depending on half life of the antibiotic - may need multiple doses a day
- Beta-lactams and Vancomycin

95
Q

What’s unique about Borrelia burgodorferi (lymes disease)?

A

It exhibits persister phenotypes - that is drug tolerant but is distinct from antibiotic resistance
Drug persistence - shift between two different genetically homogenous forms [bact. aren’t dying with the resistant strains surviving, the bacteria are all shifting between forms and later being re-cultured back into their original form]

96
Q

When does a patient need a bactericidal drug?

A

-When he/she is immunocompromised

Bactericidal = aminoglycosides, Quinupristin/Dalfopristin

97
Q

Differentiate between prophylactic, empiric and definitive therapy:

A
  1. treating an infection that has not yet developed in individuals at a high risk of developing an infection
  2. Empiric - patients who have an infection but the organism has not yet been identified
  3. Definitive - know the organisms and which drugs should work against them (narrow spectrum)
98
Q

What is competitive antagonist?

A

It is drug that causes reversible, dose-response shifts to the right, apparent affinity of agonist is reduced, slope doesn’t change, max response can still be produced (ex: acetylcholine and atropine (antagonist))

99
Q

What is a noncompetitive antagonist?

A

Irreversible, max response reduced, slope reduced, apparent affinity changes very little, if at all, apparent number of receptors decreased (for now they’re gone)

FOM Final Review (4 decks)

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