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Pharmacy School 2015-16 > PHAR 747 Exam 2 > Flashcards

PHAR 747 Exam 2 Flashcards

1
Q

Antibiotics than inhibit 30S subunit

A 
Spectinomycin 
Tetracycline 1
Pactamycin
Hygromycin B
Streptomycin
Paramomycin
Geneticin 
Tetracycline 2
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2
Q

Antibiotics that inhibit the 50S subunit

A 
Thiostrepton
Avilamycin
Streptogramin A
Chloramphenicol 
Puromycin
Pleuromutilins 
Streptogramin B
Lincosamides 
Macrolides
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3
Q

‘mycin’ vs ‘micin’

A

Mycin = Streptomyces origin

Micin = Micromonospora origin

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4
Q

Disadvantages of Streptomycin

A

Resistances emerged quickly

Ototoxic and nephrotoxic

Narrow spectrum (aerobic gram -)

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5
Q

Streptomycin was first antibiotic against ______________

A

TB

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6
Q

Aminoglycoside general properties

A

Central aminocyclitol ring with various sugars attached

2-deoxystreptamine (a modified 1,3-diaminocyclohexane) in all BUT streptamycin (has streptidine)

Basic and charged at neutral pH, highly water soluble, usually given IM or IV, some are mixtures.

Use limited to serious aerobic Gram (-)

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7
Q

Aminoglycoside Mechanism of Action

A

Penetrate outer membrane of Gram (-) actively via O2-dependent transport; can pass through porin; low pH or anaerobic conditions inhibit transport while cell wall synthesis inhibitors can enhance transport

Bind irreversibly to 16S rRNA of 30S subunit (often bactericidal); fuck up protein synthesis by causing misreading of mRNA; inhibit protein synthesis initiation and cause polsomes to dissociate into non-functional monosomes

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8
Q

Gentamicin Family

A

Mixture of 3 compounds, administered IV for serious gram (-)

Used topically for Ps. aeruginosa in burn patients or inhaled for Ps. aeruginosa in CF patients.

Cross resistance with many other AGs. Administered with carbenicillin for synergistic effect.

Physical incompatability with beta-lactams (administer with separate IVs or sequentially)

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9
Q

Members of Gentamicin family

A

Gentamicin, sisomicin, netilmicin, isepamicin

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10
Q

Kanamycin Family

A

All have kanosmine sugar at 6 position of 2-deoxystreptamine

Members: Kanamycin, Amikacin, Tobramycin

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11
Q

Kanamycin

A

Mixture of 3 compounds (mostly Kanamycin A)

Ototoxicity major problem.

Primarily used for dysentery and sometimes MDR-TB

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12
Q

Amikacin

A

Semisynthetic derivative of kanamycin A ( (S)-4-amino-2-hydroxybutyramide derivative )

Only 50% as potent as parent drug but less prone to inactivation by AG modifying enzymes.

Active against some gentamicin and tobramycin resistant strains (Mycobacterium spp.)

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13
Q

Tobramycin

A

3’-deoxykanamycin B

Used for Ps. aeruginosa but NOT active towards Mycobacteria (DO NOT USE FOR TB)

Often used as same time as antipseudomonal b-lactams (Ticarcillin, aztreonam, ceftazidine)

Active against some gentamicin resistant strains

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14
Q

Neomycin family

A

3 sugars - 2 aminohexoses and a D-ribose attached to the aminocyclitol

Members: Neomycin, Paramomycin

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15
Q

Neomycin

A

Mixture of B and C and neamine (mostly B)

One of the MOST nephrotoxic AGs

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16
Q

Paromomycin

A

Also a mixture (like Neomycin)

Used almost exclusively for amoebic dysentery; also used to treat leishmaniasis

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17
Q

Tetracyclines

A

Broad spectrum, effective against organisms resistant to agents acting on cell wall; use decreased with introduction of broad spectrum cephalosporins

In aqueous solution C-1 ketone to C-3 enol; C-10 phenol to C-12 enol; C-4 dimethylamine

Compounds with a C-6 hydroxyl undergo aicd or base promoted degredation

C-4 can epimerize in weak acid due to the b-dimethylamine

Members: Chlortetracycline, Tetracycline, Doxycycline, Minocycline, Tigecycline

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18
Q

Tetracyclines and metal ions

A

Tetracyclines can chelate many di- and trivalent metal ions.

Coordinates with Mg2+ to get through porin (gram -) and then Mg2+ released in periplasmic space. Apo-form of drug crosses cytoplasmic membrane, picks up another Mg2+ before drug binds ribosome.

If taken with dairy products, often you get poor absorption (broad spectrum combined with poor absorption = superinfection)

Tetracyclines/Ca2+ complex can be deposited in teeth and bone during gestation and early childhoold.

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19
Q

Tetracycline Mechanism of Action

A

Binds 16S rRNA of 30S ribosomal.

Blocks binding of aminoacyl-tRNA to ribosome (prevents peptide elongation, is reversible and bacteriostatic)

Toxicity selective to bacteria due to poor penetration of mammalian cells and poor affinity for mammalian ribosomes. Some bacteria will concentrate the drug in cells.

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20
Q

Chlortetracycline

A

First isolated

Only used topically now

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21
Q

Tetracycline

A

Produced by catalytic hydrogenation of chlortetracycline

Improved oral availability, high plasma concentration and long duration

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22
Q

Doxycycline

A

Lacks C-6 hydroxyl

One of most frequently prescribed tetracyclines (often for gonorrhea, syphilis, Lyme disease and malaria prevention)

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23
Q

Minocycline

A

Semisynthetic with additional dimethylamine at C-7 but no C-6 hydroxyl.

Best absorbed and longest t1/2

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24
Q

Tigecycline

A

9-tert-butyl-glycylamido derivative of minocycline

First glycylcycline (injectable only).

Not a substrate for efflux pumps that cause resistance to other tetracyclines; active against tet-resistant bacteria; more active than early tetracyclines and forms additional binding contacts with rRNA.

Resistance can develop fast in some gram (-)

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25
Q

Macrolides General Information (Natural Macrolides)

A

Large cyclic ester (lactone) composed of 12, 14 or 16 atoms; ring has numerous Me and OH groups, deoxysugar and ketone

Produced by fermentation.

Spectrum similar to penicillins and therefore often used if patient is sensitive to penicillin.

Unstable at pH 4 or less; weak bases can be formulated as salts

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26
Q

Macrolides Mechanism of Action

A

Inhibit protein synthesis by reversibly binding to 50S ribosomal subunit. Inhibits translocation of growing protein chain.

Agents do not bind to mammalian ribosomes and are usually bacteriostatic.

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27
Q

Erythromycin A

A

Acid labile, bitter and poorly absorbed when taken orally (solved with salt forms)

Erythromycin stearate - stearate salt liberated in alkaline duodenum

Erythromycin Ethyl Succinate - 2’ OH of desosamine esterified with ethyl succinate; absorbed as ester then hydrolyzed (most common oral form given)

Erythromycin Estolate - 2’OH of desosamine esterified as propionate ester and the compound is lauryl sulfate salt; acid stable

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28
Q

Second Generation Macrolides

A

Semisynthetic derivatives of Erythromycin A; developed to prevent acid degradation and improve pharmacokinetics

Potential side effects: QT interval prolongation and heart arrhythmias

Members: Azithromycin, Clarithromycin, Telithromycin

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29
Q

Azithromycin

A 
First azalide (15-membered ring with N in between C9 and C10); acid stable and better Gram (-) activity than 
erythromycin A

High tissue concentrations and given as 1g dose one time for uncomplicated gonorrhea (as effective as 7 days on doxycycline)

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30
Q

Clarithromycin

A

C6 O-Me erythromycin A

Acid stable (methylation at C6 prevents OH from participating in acid catalyzed degredation) and better absorption

2-3x potentcy of erythromycin A towards Gram (-) including Legionella spp.

2-4x more active vs gram (+) cocci than erythromycin A.

Used to treat disseminated MAC

Rapidly metabolized to 14-OH clarithromycin

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31
Q

Telithromycin

A

Semisynthetic - 1st Ketolide; Cladinose removed from clarithromycin and OH oxidized to ketone.

Ketolides do not include resistance to macrolides BUT active against many macrolide resistant strains.

Dosing: qd for 7 days to treat CAP

Can exacerbate symptoms of myasthenia gravis

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32
Q

Lincosamides

A

Clindamycin (semisynthetic) and Lincomycin (natural product)

Active towards gram (+) and some anaerobes; effective for staph in bones and joints

Can lead to fatal colitis: Superinfection by clindamycin-resistant toxin producing Clostridium sp. requires vancomycin or metronidazole

Not used for infections that are susceptible to other antibiotics

Lincosamide MOA same as macrolides

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33
Q

Oxazolidinones (SAR and MOA)

A

Eperezolid, Linezolid, Tedizolid

SAR:
3’-fluorine for activity, oxazolidinone ring must be intact

Mechanism of Action:
Bacteriostatic interruption of protein synthesis; binds 23S of rRNA of 50S near interface with 30S, blocking formation of functional 70S complex; do NOT affect peptidyl transferase activity or translation termination

No cross resistance between oxazolidinones and other antibiotics

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34
Q

Linezolid

A

Gram (+) methicillin or vancomycin resistant organisms (e.g. MRSA, VRE)

Some gram (-) activity including H. influenza and Legionella spp. but no Enterobacteriaceae or Pseudomonas spp. Also active against Mycobacterium tuberculosis and M. avium.

IV or oral (usually being IV in hospital and continue oral on discharge)

Side effects: myelosuppression (monitor blood regularly) and inhibition of monoamine oxidase (reversible and non-selective)

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35
Q

Linezolid resistance

A

Mutation in 23S rRNA gene where guanine changed to thymine

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36
Q

Chloramphenicol

A

Natural product for Streptomyces venezuelae (produced by synthesis now) - R,R form naturally occurring

Good access to the CNS - used still for bacterial meningitis.

Does not require energy-dependent transport

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37
Q

Chloramphenicol MOA

A

Acts at 50S subunit

Blocks correct binding of aminoacyl-tRNA and inhibit peptide bond formation; effect is reversible

Binding occurs near macrolide site (will compete with macrolides/clindamycin/linezolide)

Cheap, effective, broad spectrum, but has adverse effects

38
Q

DON’T COMBINE CHLORAMPHENICOL WITH?

A

Macrolides

Clindamycin

Linezolide

39
Q

Chloramphenicol adverse effects

A

High mitochondrial 70S affinity but no 80S form found in cytosol

Fatal effect on one marrow causes pancytopenia (reduction in RBCs, WBCs and platelets)

Toxicity thought to arise from metabolite involving nitrophenyl (florfenicol lacks this group)

Toxicity worse in neonates due to low glycuronosyl activity, inadequate renal excretion, resulting in high plasma concentrations. Chloramphenicol also inactivates hepatic CYP450s.

Gray baby syndrome 3-4 days after dose; hypothermic and hypotension

40
Q

Retapamulin

A

Derivative of pleuromutilin from fungus, used in vet med; semisynthetic modifications allow for better formulation and decreased metabolism

Similar type of modification that is added to quinupristin.

Approved for impetigo caused by S. aureus or S. pyogenes

41
Q

Retapamulin MOA

A

Acts at 50S subunit at unique site that involves ribosomal protein L3 in the ribosomal P site and peptidyl transferase center (inhibits peptidyl transfer, blocks P-site and prevents formation of 50S subunits)

Bacteriostatic against S. aureus and S. pyogenes but bactericidal at higher concentrations.

No specific cross-resistance

42
Q

Retapamulin Resistance

A

Efflux in some bacteria

Mutation in ribosomal L3 protein

43
Q

Fidaxomicin

A

Used against CDI with almostm no activity against normal fecal flora; minimal intestinal absorption

Equivalent efficacy and comparable safety to vancomycin for CDI (less recurrences of CDI and faster symptom resolution)

Structurally very similar to macrolide

44
Q

Fidaxomicin MOA

A

Inhibits sigma-dependent transcription of bacterial RNA polymerase

Bactericidal with prolonged post-antibiotic effect

45
Q

Quinolones/fluoroquinolons general information

A

Initially developed from impurity found during chloroquine synthesis

Used initially for UTIs; early agents most active towards gram (-)

46
Q

Quinolones/Fluoroquinolones MOA

A

Disrupt DNA replication and function - targets 2 topoisomerases ( 2 = gyrase and 4)

47
Q

DNA gyrase

A

Relaxes supercoiled DNA

Only enzyme that can also supercoil DNA

48
Q

DNA topoisomerase 4

A

Decatenating enzyme - resolves interlinked daughter chromosomes following DNA replication

Relaxes supercoil but can not induce supercoil

49
Q

Describe quinolone inhibition of Bacterial DNA gyrase

A

Gyrase and Topo4 bind dsDNA and break both strands - FQs bind this topoisomerase + broken DNA intermediate

Release of fragmented chromosome correlates with cell death; can also cause generation of hydroxyl radicals

Quinolones can only recognize and bind the topoisomerase-DNA complex

Mammaliain cells don’t have DNA gyrase and quinolones have low affinity for mammalian topoisomerase 2

50
Q

Quinolone/fluoroquinolone SAR

A

Most common heterocyclic nucleus is 3-carboxy-4-quinone

Position 2 should be unsubsituted; N-1 must have small alkyl; N can replace C at position 8 with no activity loss

Groups C5 and position 8 can affect photosensitivity

Fluorine at C6 increases activity

Substituents at C7 increase activity - piperazine extends spectrum into Ps. aeruginosa

Absorption decreased with divalent ions

51
Q

Nalidixic Acid

A

First generation (no C6 fluorine, spectrum limited to uncomplicated UTI)

First quinolone, strong acid pKa ~ 1, extensively metabolized to 7-hydroxymethyl nalidixate

52
Q

Norfloxacin

A

Second generation (increased potency and spectrum due to C6 fluorine)

First fluoroquinolone
100x more potent than nalidixic acid and broader gram (-) including Ps. aeruginosa
Some gram (+)

53
Q

Ciprofloxacin

A

2nd gen fluoroquinolone

More potent than norfloxacin and better absorbed; good distribution in bone and soft tissue; more potent vs Ps.

Good safety record = widespread use

Good serum levels allowing for use beyond genitourinary tract infections

Cyclopropane contributes to photosensitivity

54
Q

Ofloxacin and Levofloxacin

A

2nd gen fluoroquinolone

3S levo (-) isomer is most potent; 8-125x difference in potency based on species; 1,4-oxazine ring between N1 and C8

High CSF concentrations

Active vs Mycobacteria (e.g. MDR-TB)

Levofloxacin may cause QT prolongation leading to cardiovascular incidents

55
Q

Sparfloxacin

A

3rd gen fluoroquinolone

More potent against Pneumococcus and anaerobe

Difluoroquinolone; only example with C5 amine

Improved gram (+) activity

T1/2 = 8 hours

56
Q

Perks of 4th generation fluoroquinolones

A

Longer t1/2 and more potent vs Pneumococcus and anaerobes

57
Q

Moxifloxacin

A

4th gen fluoroquinolone

8-methyl-fluoroquinolone with enhanced bactericidal action, decreased rate of resistance and no P450 metabolism

Inhibit topoisomerase 4 and gyrase

Very effective against TB; NO urinary excretion so can’t be used for UTI

58
Q

Gemifloxacin

A

4th gen fluoroquinolone

Orally active and broad spectrum (gram - activity equal to ciprofloxacin but better gram +)

Indicated for CAP and acute bacterial exacerbation of chronic bronchitis.

8-30x better than ciprofloxacin against S. aureus and S. pneumoniae

Inhibitor of topo4 and gyrase in vitro

Rashes common in women under 40 and those over 40 receiving hormone replacement therapy

59
Q

General mechanisms of fluoroquinolone resistance

A

Mutations in gyrase and topo4 genes

Decreased intracellular accumulation of drug (efflux pumps, modification in membrane proteins)

In S. aureus, recG can repair damage from fluoroquinolones

60
Q

Fluoroquinolone toxicity/side effects

A

Overall safe

Can affect cartilage development (tendon rupture and tendonitis)

Qt prolongation may be related to halogen at C8

Phototoxicity with ciprofloxacin, lomefloxacin and norfloxacin (due to photodegradation products and reactive oxygen species) –> caused by cyclopropane OR halogen (skin lesion, blister, 2nd degree burn, visual disturbances)

Peripheral neuropathy

61
Q

Sulfonamide antibacterial agents general information

A

Protonsil active in vivo but no in vitro activity

Protsonil converted to aminobenzenesulfonamide (sulfanilamide) in vivo

Largely replaced by penicillins

62
Q

Sulfonamidea MOA

A

Inhibition of folic acid biosynthesis

Folate derivatives co-enzymes in important biological processes: thymidine and purine synthesis for DNA/RNA, Amino acid synthesis (Gly, Ser, Met)

Sulfonamides competitively inhibit dihydropteroate synthase (DHPS) by closely resembling natural substrate PABA –> resulting dihydropteroate derivative can’t be further transformed to tetrahydrofolate

63
Q

Inhibition of DHPS causes ______________

A

bacteriostasis

64
Q

How are sulfonamides selectively toxic?

A

Mammals do not synthesize folate and do not have DHPS

Bacteria can’t use folate from mammalian diet to replace depleted levels

65
Q

Sulfonamide general SAR

A

Sulfonamide NH is acidic (pKa 6 in most useful agents, 5-10 range) - analogs with high pHa crystalized in kidney

R2 should be small heteroaromatic ring for best activity

Aniline NH2 is essential

If R1 is not H it must be removed in vivo

66
Q

Trisulfa

A

Sulfadiazine (pKa 6.5)
Sulfamerazine (pKa 7.1)
Sulfamethazine (pKa 7.4)

Higher sulfadiazine concentrations to avoid kidney stones

67
Q

Sulfisoxazole

A

pKa 5 (most acidic sulfonamide)

Bitter but can be acetylated at the sulfonamide N to make more palatable

In sulfisoxazole acetyl, acetyl is hydrolyzed in intestines and absorbed as sulfisoxazole

68
Q

Sulfisoxazole acetyl + erythromycin = _____________

A

PEDIAZOLE

69
Q

Sulfacetamide

A

Only for topical use

Used in suspension to treat acne; drops to treat eye infection

Combined with prednisolone as BLEPHAMIDE and VASOCIDIN

70
Q

Sulfamethoxazole

A

Closely related to sulfisoxazole but not as completely or rapidly absorbed.

Commonly combined with trimethoprim for synergism (combination usually bactericidal w/ optimum ratio being 20:1 SMX:TMP)

Commercial combination product usually 5:1 ration since trimethoprim not absorbed well

71
Q

Trimethoprim MOA

A

Disrupts folate biosynthesis by inhibiting dihydrofolate reductase (DHFR)

Potent antibacterial agent alone (20-100x that of sulfamethoxazole) but resistance is rapid

72
Q

Selective difference between bacteria and mammals for sulfonamides and trimethoprim

A

IC50 for bacteria DHFR = 5nM

IC50 for mammalian DHFR = 2.6 x 10^5 nM

73
Q

Mupirocin

A

Used primarily for skin infections (impetigo) by Staphylococcus spp.

bacteriostatic but can be bactericidal at low pH

MOA: Inhibits protein biosynthesis by binding bacterial isoleucyl-tRNA synthetase (IleRS)

Selective toxicity from low affinity for mammalian IleRS; used topically due to quick inactivation by hydrolysis of fatty acid ester linkage; 95% serum bound resulting in poor bioavailability

74
Q

Metronidazole and Tinidazole

A

5-nitroimidazoles

Active against many obligate anaerobic gram (-) and gram (+); treatment for bacterial vaginosis and parasitic infections, including trichomoniasis and intestinal parasitic infections giardiasis and amebiasis

Can access the CNS

Bactericidal

Adverse effects: Can discolor urine reddish-brown; carcinogenic in rodents; selectively toxic against anaerobes and microaerophilic organisms; taking with alcohol may cause disulfiram-like reactions

75
Q

How does metronidazole reduction take place

A

Ferredoxin reduces metronidazole in single electron transfer into toxic free radical

Reduced Fd in Trichomonas vaginalis related to resistance

76
Q

Nitrofurantoin

A

Comes in capsules or oral suspension; macrocrystalline and monohydrate

Active against aerobic and facultative gram (+) and gram (-); no activity against Proteus, Serratia and Ps. spp.

MOA: Reduced by bacterial flavoprotein (nitrofuran reductase) to multiple reactive intermediates that attack DNA, proteins and other macromolecules in the cell (similar to metronidazole)

Can interfere with urine tests for glucose, can discolor urine dark yellow or brown, and are antagonistic with quinolone antibiotics in vitro

77
Q

Tuberculosis

A

Contagious airborne disease caused by Mycobacterium tuberculosis

Typically affects the lungs but may affect any other organ.

Infects nearly 1/3 of world (1 death every 15 seconds)

78
Q

Differences between Mtb infection and TB disease

A

Only 5% of those with Mtb have active TB (they will show symptoms within a few years)

90% will never get TB

79
Q

Unique problems associated with Mtb infection

A

Complex out membrane with complex glycolipids.

Slow growing (divides every 15-18h); typical therapy lasts 6-9 months with treatment extended 18-24

Intracellular bacteria that are able to colonize macrophages to avoid destruction; can remain quiescent for decades

Poor patient compliance (solved with DOTS) and widespread resistance

HIV/TB deadly as shit

80
Q

Tuberculosis resistance

A

Multidrug Resistance Mtb (resistant to isoniazid and rifampin) –> requires 18-24 months of drug therapy (regiment includes injectable aminoglycoside for 3-4 months and fluoroquinolone + any additional second line agents)

Extensively Drug Resistant Mtb: XDR TB defined as strain resistant to isoniazid and rifampin plus any fluoroquinolone and at least one of the injectable second-line agents –> requires 2 years of drug therapy

81
Q

Antitubercular Agents

A

First line drugs

Isoniazid

82
Q

Isoniazid

A

Isonicotinic acid hydrazide

Bacteriostatic versus resting cells but bactericidal against dividing organisms

Nearly idea: very selective for mycobacteria, inexpensive, good oral availability and low toxicity

Side effects: hepatotoxicity due to further metabolism of N-acetyl metabolite

Resistance develops quick in monotherapy and cross resistance is rare

83
Q

Combination formulations of Isoniazid

A

Isoniazid + Rifampin (Rifamate)

Isoniazid + rifampin + pyrazinamide (Rifater)

84
Q

Isoniazid MOA

A

Inhibits mycolic acid biosynthesis; specifically targets the enoyl-acyl carrier protein reductase (InhA) involved in mycolic acid synthesis; NADH is cofactor that INH reacts with

INH must be activated by KatG (a catalase-peroxidase) to inactivate InhA

85
Q

Rifampin

A

Derivative of rifamycin; first line treatment for all TB forms; active against rapidly dividing and semi-dormant bacterial populations

Most potent anti-TB agent (MIC as low as 5ng/mL)

Oral or parenteral; given qd or 3/week for 6 months

Activity against most gram (+); can access CNS

Side effects: GI - nausea, anorexia, discoloration of body fluids; strong CYP450 inducer

86
Q

Rifampin MOA

A

Inhibits bacterial DNA-dependent RNA polymerase; binds b-subunit

No effect on mammalian enzyme at concentrations under 5 micrograms/mL

87
Q

Rifabutin

A

Substitute for rifampin in treatment of all TB forms (reserved for those who are taking medications that react with rifampin)

Primarily used to treat M. avium complex, AKA MAC (or M. intracellulare)

MAC symptoms similar to chronic bronchitis (over 40% of AIDS patients become infected) –> Rifabutin often prescribed as a preventative measure in those with HIV/AIDS

88
Q

Rifapentine

A

Cyclopentyl derivative of rifampin

Advantage is less frequent dosing than rifampin (2/week for intensive phase, 1/week after)

Long t1/2

89
Q

Rifaximin

A

Indicated for traveler’s diarrhea

Less than 1% of an oral dose absorbed

Use is for noninvasive enteroaggregative E.coli

90
Q

Ethambutol

A

Synthetic; bacteriostatic; active only towards actively dividing cells

Good oral availability and well tolerated

Synergism with rifampin (may enhance intracellular access of rifampin)

Helps prevent emergence of rifampin resistance when primary INH resistance may be present

Side effects: decreased visual acuity or red-green color discrimination; effect is dose related; not recommended for children who cannot read eye charts

91
Q

Ethambutol MOA

A

Inhibits Mtb cell wall biosynthesis by inhibiting arabinosyltransferase and thus formation of cell wall arabinogalactan; may interfere with transfer of arabinose to cell wall acceptor

Causes accumulation of lipid carrier decaprenyl phosphoarabinose

Pharmacy School 2015-16 (34 decks)

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