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Pharmacology-TJA > Exam 2 > Flashcards

Exam 2 Flashcards

0
Q

Tetracyclines: Target/mechanism

A

Binds reversibly to aminoacyl-tRNA acceptor site of 30s subunit on mRNA-ribosome complex.

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1
Q

Tetracyclines: drug list

A

“To destroy micro’s 30s”

Tetracycline, doxycycline, minocycline, tigecycline

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2
Q

Which categories of bacteria are Tetracyclines active against? Are they bacteriastatic or bacteriacidal?

A

Bacteriastatic against gram+ and gram-. No activity against Pseudomonas, Proteus, or Staph species.

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3
Q

Tetracyclines: Indication(s)

A

Rarely first line therapy. Exceptions are R. rickettsii (Doxy) and B. bergdorferi (Lyme Doxy or Mino). Can be used instead of Azithromycin along with ceftriaxone (250mg IM)

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4
Q

Tetracyclines: ADME/route

A

All can be given PO except tigecycline. Tigecycline and doxycycline can be given IV. Minocycline can also be topical for acne. Absorption is inhibited by divalent cations, so don’t take with milk or antacid. Tetracycline is eliminated through renal and biliary, the rest are biliary only and therefore are safe for patients with impaired renal function.

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5
Q

Tetracyclines: toxicity

A
  1. Nausea, vomiting
  2. Hepatic toxicity (high doses or pts with renal failure)
  3. Vestibular dysfunction (high doses)
  4. Renal toxicity (if expired)
  5. Superinfection
  6. Stains teeth (chetelation of divalent cations)
  7. Can interfere with effectiveness of oral contraception.
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6
Q

Tetracyclines: Contraindications

A

Pregnancy teratogenicity category D. Children (because of teeth staining).

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7
Q

Aminoglycosides: drug list

A

Streptomycin, gentamicin, neomycin, amikacin

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8
Q

Aminoglycosides: Target/mechanism

A

Target 30s subunit of ribosome 3 ways: 1. block initiation of protein synthesis; 2. terminate translation prematurely; 3. substitute different amino acids than what is coded for.

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9
Q

Aminoglycocides (-ycins): have activity against…

A

Aerobic gram- (esp Psudomonas, Acenitobacter, Enterobacter)

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10
Q

Aminoglycocides (-ycins): ADME

A

Cationic at physiologic pH, so NOT PO. IM, IV, inhaled, or topical. Not metabolized. Remains in tissue AFTER elimination from plasma. Only crosses blood-brain barrier in inflammation (intrathecal route preferred for meningitis). Renal elimination.

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11
Q

Aminoglycosides (-mycin): Indicated for (4 categories)

A

Enteric aerobic gram-‘s, inc Pseudomonas, Acenitobacter, Enterobacter (severe infections), Yersinia pestis, and synergistic with beta-lactams for endocarditis caused by strep, staph, enterococci, and TB (2nd line, Streptomycin, Amikacin)

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12
Q

Aminoglycosides: toxicity

A
  1. Ototoxicity: vestibular and high frequency hearing loss (20%)
  2. Nephrotoxicity: especially with other nephrotoxins (25%)
  3. Neuromuscular blockade- apnea and respiratory depression.
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13
Q

Aminoglycocides: contraindication

A

Teratogenicity category D (contraindicated in pregnancy)

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14
Q

Chloramphenicol: target/mechanism

A

Inhibits peptidyltransferase in 50s subunit of ribosome, preventing peptide bond formation during translation. Also affects Eukaryotic ribosome.

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15
Q

Chloramphenicol: Activity

A

First broad-spectrum. Has bacteriaSTATIC activity against anaerobes and aerobes, gram+, and gram-. Bacteriacidal against H. influenzae, N. meningitidis, and S. pneumoniae.

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16
Q

Chloramphenicol: indication

A

It is rarely used in the US, but still used abroad. Oral preps not available here. Can be used for bacterial conjuctivitis.

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17
Q

Chloramphenicol: ADME

A

Readily absorbed through oral route, but also administered IV. Large volume of distribution, enters CNS. Metabolized in liver by Cyp2C and cyp3A (inhibitory) and glucaronidated. Primarily renal elimination.

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18
Q

Chloramphenicol: Toxicity

A
  1. Hematopoetic toxicity- aplastic anaemia (effect on ribosomes)
  2. Gray baby syndrome in neonates
  3. Drug interactions via P450 inhibition (ex warfarin, PIs)
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20
Q

Chloramphenicol: contraindication

A

Teratogenicity category D (don’t use in pregnancy). Contraindicated for neonates because they lack UDP-glucuronsyltransferase, which inhibits excretion.

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21
Q

Which drugs classes are cell wall inhibitors?

A

Penicillins, cephalosporins, carbapenams, monobactams, vancomycin

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22
Q

Which drug classes have beta lactam structure?

A

Penicillins, cephalosporins, carbapenams, monobactams.

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23
Q

Penicillins: drug list

A

penicillin G, navcillin, amoxicillin, piperacillin, amoxicillin + clavulanic acid (all have “cillin” ending)

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24
Q

Penicillins: target/mechanism

A

Target: peptidoglycan transpeptidase. All beta-lactam antibiotics have this target. It is essentially a suicide inhibitor

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25
Q

Penicillin G: Activity against

A

Bacteriacidal against susceptible gram+ aerobes. Includes streptococci, meningococci, enterococci and non-beta lactamase producing staphylococci.

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26
Q

Penicillin G: ADME

A

25% oral absorption, so usually injected. Widely distributed, but poor CNS penetration (unless meninges are inflamed). Renal excretion (like all beta-lactams)

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27
Q

Penicillins: Toxicity

A

Low direct toxicity because of high target specificity. Diarrhea, thrombophlebitis (injected), CNS-tremors (rare, and at high doses), superinfection. Hypersensitivity is relatively common, anaphyllaxis being the most serious. Can occur immediately (0-30 mins), or Accelerated (1-72 hr). Delayed reactions (3-30 days) are usually self-limiting skin reactions, but can include serum sickness, hemolytic anemia and Stevens-Johnson Syndrome.

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28
Q

What drug is most commonly substituted for Penicillin in case of hypersensitivity?

A

Erythromycin.

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29
Q

Nafcillin: Activity against

A

Bacteriacidal against same spectrum of activity as penicillin G (gram + aerobes), but can treat penicillinase-producing strains of S. aureus.

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30
Q

Nafcillin: ADME

A

Mainly IV (oral absorption is erratic). Distribution and metabolism same as penicillin. Biliary excretion.

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31
Q

Penicillins: contraindication

A

Contraindicated in case of hypersensitivity to beta-lactams and possibly serious kidney disease.

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32
Q

Amoxicillin: Activity against

A

gram+ AND gram-, but disabled by beta-lactamase (unless given with clavulanic acid). Includes: H. influenzae, E. coli, Listeria, Proteus, Salmonella, Shigella, enterococci.

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33
Q

Amoxicillin: ADME

A

PO or IV. Renal excretion.

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34
Q

Piperacillin: activity against, ADME

A

Has activity against select gram negatives, basically used to treat Pseudomonas. Inactivated by beta-lactamase and gastric acid, so route is IV or IM. Excretion is 80% renal.

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35
Q

Cephalosporins: drug list

A

cef/ceph/ceft. Cefazolin, cephalexin (gen 1), cefoxitin (gen 2), ceftriaxone, ceftazidime (gen 3)

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36
Q

Cephalosporins: target/mechanism

A

Identical to penicillin: targets peptidoglycan transpeptidase.

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37
Q

Cefazolin, cephalexin: activity against

A

gram+ cocci, limited gram negatives. Generally ok with beta-lactamase producing organisms.

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38
Q

Cefazolin, cephalexin: Indication

A

Work well against skin and soft tissue infections (eg: staph aureus, strep)

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39
Q

Cefazolin, cephalexin: ADME

A

Cefazolin: parenteral. Cephalexin: oral (well absorbed). Neither penetrates well into the CNS. Excreted by kidney.

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40
Q

Cephalosporins: Toxicity

A

Same as penicillin, PLUS Mild nephrotoxicity, and enhanced nephrotoxicity with aminoglycocides.

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41
Q

Cephalosporins: Contraindication

A

Contraindicated in beta lactam allergy and possibly serious kidney disease.

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42
Q

Cefoxitin: activity against

A

This second generation cephalosporin is relatively more resistant to beta-lactamases than earlier generations. It is bacteriacidal but still only active against gram+ and select gram-.

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43
Q

Cefoxitin: indication

A

some mixed gram+/- infections like PID and lung abcess, as well as surgical prophylaxis for infections caused by gram-‘s

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44
Q

Ceftriaxone and Ceftazidime: activity against

A

Third generation cephalosporin is bacteriacidal against gram- bacteria that are resistant to other beta lactams.

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45
Q

Cefoxitin: ADME

A

route is IV. Does not penetrate CNS. Excreted by kidney.

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46
Q

Ceftriaxone, Ceftazidime: indications

A

Ceftriaxone: drug of choice for gonorrhea and severe Lyme. Also used for meningitis.

Ceftazidime: Pseudomonas aeruginosa

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47
Q

Ceftriaxone, ceftazidime: ADME

A

Route is parenteral for both (IM, IV). Good CNS penetration. Renal excretion.

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48
Q

Extended spectrum beta-lactamase

A

Confers resistance against both penicillins and 3 generations of cephalosporins.

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49
Q

Carbapenems: Drug list

A

imipenem-cilastatin, meropenem

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50
Q

Carbapenems: target/mechanism

A

same as all beta-lactams: (peptidoglycan transpeptidase).

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51
Q

Carbapenems: Activity against

A

These have the broadest spectrum of all antibiotics. Bacteriacidal against gram+ and gram-.

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52
Q

Carbapenems: ADME

A

IM, IV routes only. Imipenem is deactivated by dehydropeptidase I in Kidney (but this enzyme is inhibited by cilastatin). Little crosses into CNS. Renal excretion.

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53
Q

Carbapenems: Toxicity

A

Hypersensitivity (like other beta-lactams), Seizures in patients with CNS lesions or renal dysfunction. Nausea, vomiting.

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54
Q

Carbapenems: contraindication

A

Beta-lactam allergy. Cross-allergenic with penicillin and cephalosporin.

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55
Q

Monbactams: Drug list

A

Aztreonam

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56
Q

Aztreonam: Target/mechanism

A

same as all beta-lactams: (peptidoglycan transpeptidase).

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57
Q

Aztreonam: activity against

A

Bacteriacidal against aerobic gram- bacteria. Good activity against enterobacteriaceae and Pseudomonas. Resistant to most beta-lactamases.

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58
Q

Aztreonam: ADME

A

Route is IV, IM, or inhaled. It does not cross into the CNS. Renal elimination.

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59
Q

Aztreonam: Toxicity

A

Thrombophlebitis at injection site. Some hypersensitivity, but not cross-allergenic with penicillins or cephalosporins.

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60
Q

Aztreonam: contraindication

A

Hypersensitivity to aztreonam (not penicillins or cephalosporins).

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61
Q

Vancomycin: target/mechanism

A

Cell wall inhibitor. Specifically, target is peptidoglycan synthetase by binding to D-Ala terminus.

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62
Q

Vancomycin: activity against

A

Bacteriacidal against Gram + ONLY. Typically, not a first line therapy.

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63
Q

Vancomycin: indication

A

Used orally in treatment of pseudomembranous colitis.

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64
Q

Vancomycin: ADME

A

Not absorbed orally (IV only). Does not penetrate CNS. Renal excretion, not removed by hemodyalysis (half life is 6-10 days in these patients).

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65
Q

Vancomycin: Toxicity

A

Thrombophlebitis at site of injection, chills/fever, Ototoxicity (if in large doses or with another ototoxic drug), flushing (can be inflused slower or given with 1st gen antihistamine), nephrotoxicity at higher doses. Red man syndrome.

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66
Q

Macrolides: drug list

A

‘thromycin’: erythromycin, clarithromycin, azithromycin

67
Q

Macrolides: target/mechanism

A

50s subunit inhibitors of bacterial ribosome. Prevent translocation step in elongation. Specifically, targets L15 protein in 50s.

68
Q

AMINOS

A 
acronym for aminoglycocides: 
A aerobic gram negative 
M modified enzymes cause resistance 
I irreversible inhibitors of 30s
N nephrotoxic
O ototoxic
S synergistic with beta lactams
69
Q

SULFA

A 
acronym for sulfas
S skin rash / Stevens Johnson syndrome 
U UTI's
L large spectrum G+\-
F folate synthesis inhibitors 
A analog of PABA
70
Q

Sam’s “5 Cs” of tetracyclines

A

C CI in children <8
C CI in childbirth (pregnancy)
C chelate divalent cations (like Ca2+) leading to bone damage and staining teeth
C chlamydia
C causes C diff / candida via superinfection

71
Q

Sam’s “4 L’s” of linezolid

A

Low blood contents (anemia, thrombocytopenia, leukopenia)
Loose stool (diarrhea)
Losing your lunch (nausea, vomiting)
Lumpy skin (rash)

72
Q

TRON

A 
accronym for the side-effects of vancomycin: 
T thrombophlebitis 
R red man syndrome 
O ototoxic 
N nephrotoxic
73
Q

Sam’s 4C’s of cipro

A

C concentration dependent killing
C complicated UTI’s
C cartilage damage
C psyChosis

74
Q

Crazy Lucy

A

Acronym for fluoroquinolones
Crazy (Ciproflaxin) = causes acute psychosis w/ NSAIDS
Lucy (Levoflaxin)

75
Q

Diarrhea loves meds

A

Accronym for ABs used against Vancomycin resistant microorganisms.
Diarrhea (Daptomycin)
Loves (linezolid)
Meds (Metronidazole)

76
Q

Cunning Pseudomonas aeruginosa

A

Accronym for ABs aginst Pseudomonas
Cunning (Ceftazidime)
Pseudomonas (Pepicillin)
Aeruginosa (Aztreonam)

77
Q

Macrolides: activity against

A

BacteriaSTATIC activity gram +’s as well as mycoplasma, legionella (-), Chlamydia (-). Gram + organisms accumulate 100x more than gram-.

78
Q

MLS Phenotype

A

A mutation in bacterial 50s ribosome (methylation) that prevents effective binding of macrolides, lincosamides, and streptogramins (all bind to same site)

79
Q

Erythromycin: ADME

A

Oral (requires gastric coating, food interferes with absorption) or parenteral routes. Usually administered as a prodrug. Widely distributed, but does not enter CNS. Metabolized by P450(cyp4A) in liver (P450 inhibitor). Biliary excretion. SHORT half-life (1.5h)

80
Q

Erythromycin: toxicity

A

GI intolerance due to direct stimulation of gut motility, liver toxicity, reversible hearing loss (in high doses), QT prolongation (usually in combination with other drugs. Interactions through cyp3A4

81
Q

Erythromycin: contraindication

A

In those with known hypersensitivity. OK in kids, pregnancy category B.

82
Q

Clarithromycin: ADME

A

More stable in acid than erythromycin. Wide distribution, does not enter CNS. Metabolized in liver (active metabolite), and is a cyp3A4(p450) inhibitor. RENAL elimination. Dose reduction is required in severe liver OR kidney disease.

83
Q

Clarithromycin: Toxicity

A

TERATOGENIC. GI intolerance (<Erythromycin), reversible hearing loss (high doses), interactions with other drugs (cyp3A4 inhibitor).

84
Q

Clarithromycin: Contraindications

A

Pregnancy, macrolide hypersensitivity, or with drugs it interacts with (includes statins).

85
Q

Clarithromycin: indication

A

H. Pylori (along with amoxicillin) because it is more stable in stomach.

86
Q

Azithromycin: ADME

A

Mainly oral because it is stable in acid, but there are IV preps. Distributes deep into tissues (10-100x higher concentration than plasma), but not into CNS. Metabolized in liver, but does NOT inhibit P450. Primarily biliary excretion, but some is excreted in kidney. 3 day half life (drug accumulates in tissues, then is slowly released back into plasma).

87
Q

Azithromycin: toxicity

A

Well tolerated orally, but food decreases bioavailability. Antacids delay absorption. VERY few drug-drug interactions.

88
Q

Azithromycin: contraindications

A

Very few interactions or adverse events. Hypersensitivity is primary contraindication.

89
Q

Lincosamides: drug list

A

Clindamycin only

90
Q

Clindamycin: target/mechanism

A

Same mechanism as erythromycin, but structurally distinct. 50s subunit inhibitors of bacterial ribosome. Prevent translocation step in elongation. Specifically, targets L15 protein in 50s.

91
Q

Clindamycin: activity against

A

bacteriaSTATIC activity against most gram+’s (not C. diff) and gram- ANAEROBES (enterococci are also not susceptible).

92
Q

Clindamycin: indication

A

MRSA, serious infections by Bacteroides, and mixed infections with anaerobes.

93
Q

What is special about Clindamycin resistance?

A

Clindamycin can induce resistance to macrolides and vice-versa.

94
Q

Clindamycin: ADME

A

Oral and parenteral routes. Distributes into most tissues (not CNS). Metabolized by liver (not a p450 inhibitor, but dosage adjust in hepatic disease). Biliary (80%) and renal (20%) excretion.

95
Q

Clindamycin: Toxicity

A

Diarrhea, nausea, skin rashes, pseudomembranous colitis.

96
Q

Clindamycin: contraindication

A

Do not coadminister with macrolides.

97
Q

Metronidazole: target/mechanism

A

Destroys DNA once it has been reduced (which only occurs in anaerobic bacteria)

98
Q

Metronidazole: Activity against

A

BacteriaCIDAL against Claustridium difficile, other anaerobes. Resistance in bacteria with reduced levels of nitroreductase. Also active against amoebas and protazoa.

99
Q

Metronidazole: Indication

A

Pseudomembranous colitis due to Claustridium difficile, several parasitic infections (including amoebas and giardia)

100
Q

Metronidazole: ADME

A

Oral, IV routes (topical preps also available). Distributes widely and penetrates CNS. Metabolized in liver, inhibits P450 and aldehyde dehydrogenase causing toxicity when consumed with alcohol. Renal (70%) and biliary excretion (30%).

101
Q

Metronidazole: toxicity

A

nausea, headache, dry mouth with metallic taste. Turns urine reddish brown. CNS effects: vertigo, paresthesias, dizziness.

102
Q

Metronidazole: contraindication

A

Contraindicated during 1st trimester of pregnancy. Drug interactions with P450.

103
Q

Linezolid: target/mechanism

A

Binds to 23S RNA of the 50s bacteria subunit, preventing 70s complex formation. Rarely cross-resistant with other protein synthesis inhibitors because of a unique binding site.

104
Q

Linezolid: activity against

A

Gram positives mostly. Useful in vancomycin resistance.

105
Q

Linezolid: Indication

A

Infections due to vancomycin-resistant organisms

106
Q

Linezolid: ADME

A

Oral and parenteral routes. Widely distributed (good CNS penetration). Metabolized in liver (not p450), renal excretion. No dosage adjustment recommended for renal dysfunction.

107
Q

Linezolid: toxicity

A

nausea, vomiting, diarrhea, headache, rash. Myelosuppression, including anemia, leukopenia, and thrombocytopenia. Peripheral and optic neuropathy with prolonged use (reversible). Inibits monoamine oxidase, so can cause hypertension if taken with tyramine rich foods. Do not take with pseudophedrine or SSRI’s. No p450 interactions.

108
Q

Daptomycin: mechanism/target

A

Unique mechanism that requires physiologic levels of calcium. Forms an ion-conducting pore in bacterial cell wall.

109
Q

Daptomycin: activity against

A

bacteriaCIDAL against vancomycin resistant garm+’s

110
Q

Daptomycin: indication

A

Use only for vancomycin resistant infections. MRSA.

111
Q

Daptomycin: ADME

A

IV only. Does not cross into CNS. Not metabolized. Renal excretion (dosage adjust for renal function).

112
Q

Daptomycin: Toxicity

A

GI, injection site reactions, fever, HA, insomnia, dizziness, rash. At high doses increases creatin phosphokinase, causing muscle weakness, discomfort.

113
Q

Daptomycin: contraindication

A

Associated with rhabdomyolysis in combination with statins and other drugs that increase risk.

114
Q

Sulfonamides: accronym/drug list

A

Sulfas (Sulfisoxazol)
Stop & (sulfamethoxazole) = “&” means the addition of another drug aka TMP
Combat (Cotrimazole)
Dihydrofolate-Synthase (Dapsone)

115
Q

Sulfonamides: target/mechanism

A

inhibit folate synthesis, and therefore prevent bacteria DNA replication. Synergistic effect when combined with a dyhydrofolate reductase inhibitor like trimethoprim or pyrimethamine.

116
Q

Sulfonamides: activity against

A

BacteriaSTATIC alone, but bacteriaCIDAL when combined with trimethoprim (TMP). Effective against gram+ AND gram-, but NOT anaerobes.

117
Q

Sulfonamides: indication

A

uncompliated UTIs, respiratory tract infections, GI infections, pneumocystis jiroveci.

118
Q

Sulfonamides: ADME

A

Readily absorbed through GI tract, highly protein bound. Penetrate CNS, CSF. Metabolized in liver by CYP2C8/9 forming inactive metabolites. Renal elimination (dosage adjust in renal impairment). Only Sulfadoxine has a long half-ife (100-230 hours).

119
Q

Sulfonamides: Toxicity

A

Hematopoietic toxicity (hemolytic/aplastic anemia), Hypersensitivity, a few others like crystalization of urine.

120
Q

Sufonamides: contraindication

A

do not use in pregnancy or in neonates (bind to albumin and displace bilirubin, leading to life-threatening kernicterus).

121
Q

Fluoroquinolones: drug list

A

Ciprofloxacin, Levofolxacin (2nd line against TB)

122
Q

Ciprofloxacin: mechanism/target

A

competitive inhibitor of DNA gyrase (gram-) and DNA topoisomerase IV (gram+). Also able to inhibit human topoisomerase II, but only at much higher concentrations.

123
Q

Ciprofloxacin: activity against

A

Concentration-dependent killing against gram+ AND gram-‘s. Not effective against anaerobes, MRSA, EIEC, S pneumo.

124
Q

Ciprofoxacin: indication

A

complicated UTIs, sinusitis, and respiratory infections.

125
Q

Ciprofloxacin: ADME

A

Readily absorbed after oral administration, but can be impaired by divalent cations (antacids). Highest penetration into kidney lung, gallbladder; lowest into prostate, CSF, and bone. Does penetrate CNS. Metabolized in liver by P450. Renal elimination.

126
Q

Ciprofloxacin: toxicity

A

Nausea, vomiting, C. Diff superinfection. Cartilage damage is rare, as are CNS effects.

127
Q

Ciprofloxacin: contraindication

A

Pregnancy, children. Do not use with NSAIDs, and use caution with antiarrhythmics.

128
Q

Urinary antiseptics: drug list

A

Methenamine, Nitrofurantoin

129
Q

Methenamine: how does it work?

A

Poorly absorbed after oral administration and concentrates in the urinary tract. In acidic urine (pH<5.5) it undergoes decomposition to yield formaldehyde, a very effective protein crosslinking inhibitor. Not a first line agent. It is contraindicated in patients with impaired hepatic function and in renal insufficiency if combined with acids to lower urine pH. There is no mechanism of resistance except raising urinary pH (which Proteus can do).

130
Q

Nitrofurantoin: how does it work?

A

Although it is well absorbed, it is extremely rapidly eliminated in the urine (no systemic effects). It is bacteriaSTATIC against E. coli and enterococci, which produce a DNA damagin metabolite after enzymatically reducing. Resistance is common among Proteus, Pseudomonas, and Enterobacter. While it turns urine brown, it does not cause nephrotoxicity. Side effects include GI discomfort, hepatic toxicicty, pulmonary toxicity, and neurological effects.

131
Q

What are the first line anti-TB drugs for active TB?

A

2 months of RIPE: Rifampin, Isoniazid (INH), Pyrazinamide, Ethambutal (if INH resistance is suspected). If it hasn’t cleared after 2 months, then add 4 additional months of INH and RIF.

132
Q

What is the preferred treatment for LATENT TB?

A

9 months of isoniazid OR Rifampin

133
Q

MACROLIDES: accronym

A 
M - methylation - resistance
A - Azithromycin does not inhibit P450
C - clarithromycin is teratogenic
R - renal elimination
O - oral administration
L - long QT (erythromycin)
I - inhibition of translocation at the 50s subunit is the mechanism
D - DDI's due to p450 inhibition
E - Erythromycin is 1st choice for PCN allergies
S - bacterioSTATIC
134
Q

5 Treatment challenges for TB:

A
  1. Cell wall is lipid rich (mycolic acid) and is impermeable
  2. Abundance of efflux pumps
  3. Intracellular (with in macrophages)
  4. Slow growing
  5. Latent infection is common
135
Q

Second-line drugs for TB

A

Bedaquiline (MDR), Streptomycin, Amikacin, Levofloxacin, Cycloserine.

136
Q

Streptomycin: target/mechanism in TB

A

Protein synthesis inhibitor, targets 30s ribosomal subunit. This is the same mechanism as other aminoglycosides. It is bacteriaCIDAL, but cannot enter cells.

137
Q

Streptomycin: indication for TB

A

Resistance is widespread, so it’s use is reserved for severe cases (disseminated disease, meningitis) where several agents must be used. Oldest anti-TB drug.

138
Q

Isoniazid: target/mechanism (is it CIDAL?)

A

Isoniazid is a prodrug which is activated by mycobacterial KatG. It then inhibits synthesis of mycolic acid for cell wall construction by FAS2. It is bacteriaCIDAL against replicating organisms.

139
Q

Isoniazid: ADME

A

Administered orally where it is readily absorbed. Distribution is wide and includes good CNS penetration AND penetrates macrophages. It is metabolized (acetylated) in the liver, though the rate (and half-life) are dependent on patients genes (slow vs fast). p450 inhibitor. Clearance is Renal. INH is the most effective anti-TB drug in susceptible organisms.

140
Q

What is the rough breakdown between slow and fast acetylators in the US? What causes the difference? How do their origins vary?

A

NAT2 is the hepatic enzyme responsible for acetylation of INH, which marks it for excretion. It is about 50/50, with slow acetylators coming from Scandinavian, Jewish, and North African Caucasian ancestory. Inuit and Japanses are typically fast acetylators.

141
Q

INH: toxicity (3 serious categories)

A

Rash, fever are common. 10-20% have hepatic toxicity (though less than 3% will have hepatitis), which may be potentiated by rifampin. More common in those over 35 y/o, and less common in fast acetylators. Peripheral neuropathy is another. INH competes with pyridoxine (B6) for renal reabsorption and it can cause deficiency. HIgher incidence in slow acetylators. Administor pyridoxine with INH. Finally, it is a p450 inhibitor, and therefore has several interactions with other drugs, including acetaminophen, which increases risk of hepatotoxicity.

142
Q

Pyrazinamide: target/mechanism

A

Also a prodrug (like INH), which is converted by mycobacterial pncA (pyrazinamidase) to it’s active form. Target is FAS1, which is essential for bacterial synthesis of fatty acids (inc. mycolic acid). It is an NADH antagonist. BacteriaCIDAL.

143
Q

Pyrazinamide: ADME

A

oral administration. Distributed widely, INCLUDING CNS. It is inactive at neutral pH, but becomes activated when it reaches the acidic edge of the TB cavity. It penetrates macrophages and is excreted renally.

144
Q

Pyrazinamide: Toxicity

A

Causes hyperuricemia, which exacerbates gout. Also can cause hepatic toxicity. Nausea, vomiting, fever, arthralgias are other common side effects.

145
Q

Isoniazid: contraindication

A

Pregnancy category C (not approved).

146
Q

Pyrazinamide: contraindication

A

Avoid in patients with hepatic dysfunction. Pregnancy category C.

147
Q

Ethambutol: target/mechanism

A

Inhibits mycobacterial arabinosyl transferases (embAB), which prevents polymerization of bacterial cell wall. Essentially this enhances cell wall permeability. It is not bacteriacidal (bacteriaSTATIC) by itself, but increases entry of other drugs.

148
Q

Ethambutol: toxicity

A

Optic neuritis with loss of visual acuity or red-green colorblindness. Fever, rash.

149
Q

Ethambutol: ADME

A

Orally administered. Does not penetrate CNS unless there is meningeal inflammation. Metbolized in liver, but 50% is excreted unchanged. Renal elimination.

150
Q

Rifampin: target/mechanism

A

Inhibits bacterial RNA synthesis by binding to RNA polymerase (rpoB). BacteriaCIDAL.

151
Q

Ethambutol: contraindication

A

none listed. Pregnancy category B.

152
Q

Rifampin: ADME

A

Oral administration with little CNS penetration (due to protein binding). Penetrates macrophages. Hepatic/biliary metabolism AND clearance.

153
Q

Rifampin: toxicity

A

Nausea, vomiting, fever, rash. Can turn urine, tears, and other fluids reddish-orange (can stain lenses).

154
Q

Rifampin: contraindication

A

It is a p450 (CYP3A4) INDUCER, enhancing metabolism of several anti-HIV drugs and DECREASING half life of many other drugs (inc oral contraceptives). It is pregnancy category C.

155
Q

MDR TB- definition

A

Resistance to Rifampin and Isoniazid.

156
Q

Generally, how do you treat MDR TB?

A

4-6 drugs, including injectables, for a minimum of 18 months. Choose drugs based on evidence of susceptibility.

157
Q

Bedaquiline: target/mechanism

A

Inhibits mycobacterial ATP synthase.

158
Q

Bedaquiline: ADME

A

Oral administration. No CNS penetration (high protein binding). Metabolized by CYP3A4 and has a 5.5 month half-life. Biliary excretion.

159
Q

Bedaquiline: toxicity

A

Nausea, anorexia, increased hepatic transaminases (monitor liver enzymes). Increased risk of death due to increased QT interval.

160
Q

Bedaquiline: contraindication

A

Only used to treat MDR TB. Do not administer with a significant CYP3A4 inducer(rifampin) or inhibitor. Pregnancy category B.

161
Q

XDR-TB definition

A

Resistant to INH, RIF, any fluoroquinolone, and at least one second-line IV drug (eg aminoglycoside).

162
Q

How do you treat M. avium?

A

Macrolide (azithromycin/clarithromycin) + Ethambutal + Rifamycin (rifabutin/rifampin)

163
Q

Standard treatment regimen for M leprae

A

Dapsone + Clofazimine + Rifampin

164
Q

Just for fun, list all the antibiotics that are contraindicated in pregnancy: (Some Treatments Are Contraindicated For The Childbearing Mother)

A 
Some- Sulfonamines
Treatments- Trimethoprim
Are- Aminoglycosides
Contraindicated- Clarithromycin
For- Fluoroquinolones
The-Tetracyclines
Childbearing- Chloramphenicol
Mother- Metronidazole

Pharmacology-TJA (6 decks)

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