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Pharm2Exam3 Flashcards

1
Q

Beta Lactams

A 
Penicillins
Cephalosporins
Carbapenems
Monobactams
Beta-Lactamase Inhibitors
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2
Q

Penicillins (drugs)

A 
Penicillin G (IV)
Penicillin V (PO)
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3
Q

Penicillin Coverage

A

Streptococcus

Syphilis

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4
Q

Aminopenicillins (drugs)

A

Amoxicillin

Ampicillin

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5
Q

Penicillin Pharm

A

Protein bound
low BV (poor diffusion) low CSF, brain, prostate, eye, etc. concentration
Little hepatic metabolism
Eliminated renally

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6
Q

Amoxicillin Spectrum

A

Strep, no staph, Enterococcus faecalis, no MRSA, no G-, Haemophilius influenzae (G-)

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7
Q

Ampicillin Spectrum

A

Strep, no staph, Enterococcus faecalis, Listeria, no G-, Haemophilius influenzae (G-)

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8
Q

Anti-staphylococcal Penicillins (drugs)

A

Methicillin
Nafcillin
Oxacillin
Dicloxacillin

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9
Q

Anti-staph penicillin coverage

A

Staph, strep, no Enterococcus, No MRSA, little G-

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10
Q

Extended Spectrum penicillins

A

Piperacillin

Ticarcillin

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11
Q

Extended Spectrum penicillin coverage

A

Streph, minimal staph, Enterococcus faecalis, No MRSA, G- coverage**, Pseudomonas, some anaerobes

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12
Q

Beta-lactamase inhibitors (drugs)

A

Amoxicillin/Clavulanate
Ampicillin/Sulbactam
Pipercillin/Tazobactam
Ticarcillin/Clavulanate

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13
Q

Amoxicillin/Clavulanate

A

Staph, strep, E. facealis, G-! Neisseria, E coli, Proteus, Morexella, Hemophilus influenzae, Klebsiella, and anaerobes

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14
Q

Amoxicillin/Clavulanate

A

Staph, strep, E. facealis, G-! Neisseria, E coli, Proteus, Morexella, Hemophilus influenzae, Klebsiella, and anaerobes

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15
Q

Ampicillin/Sulbactam

A

Similar to amoxicillin/clavulanate + acinetobacter

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16
Q

Piperacillin/Tazobactam

A

Beta-lactamase inhibitor

Staph. strep, E faecalis, no MRSA, broad G-***, pseudomonas, anaerobes

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17
Q

Ticarcillin/clavulanate

A

Same as pipercillin/tazobactam

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18
Q

Penicillin Tox

A 
Mainly tolerable
*Allergies - anaphylaxis, urticaria, fever, swelling, hemolytic anemia, vasculitis
Penicillin: Seizures*
Nafcillin: Myelosuppression
Oxacillin: Hepatitis
*Large PO doses = GI tox
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19
Q

Beta-lactam Resistance Mech.

A

Altered PBPs, reduced permeability, Beta-lactamases

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20
Q

Type 1 Beta Lactamase

A

Cephalosporinase
Hydrolyzes: beta-lactamase inhibitor/beta-lactam combo drugs, penicillins, 1/2/3 gen cephalosporins, monobactams
Treatments: Imipenem, fluoroquinolones, and cefepime

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21
Q

Type II Beta Lactamase

A

Extended Spectrum Beta-lactamases
Hydrolyzes: cephalosporins (except cefoxitin, cefmetazole, and cefotetan), Aztreonam, Extended spectrum penicillins!, combo penicillins kind of work
Treatment: Carbapenems, Non-beta lactams, Cephamycins

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22
Q

Type III Beta Lactamases

A

Metallo-beta-lactamases
Hydrolyzes: Carbapenems!!, older penicillins, cefotaxime, ceftriaxone
Treatment: Piperacillin, ceftazidime, some combo penicillins

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23
Q

1st Gen cephalosporins

A

Cefazolin
cephalexin
Cefadroxil

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24
Q

1st Gen cephalo Spectrum

A

NO ENTERO, staph, strep, NO MRSA, G-: proteus, e coli, klebsiella

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25
1st Gen cephalo Spectrum
NO ENTERO, staph, strep, NO MRSA, G-: proteus, e coli, klebsiella
26
2nd Gen Cephalosporins
``` Cefuroxime Cefaclor Cefprozil Cefoxitin Cefotetan Cefmetazole Cefimandole ```
27
2nd gen Cephalo spectrum
staph, strep, no entero, less G+ that 1st gen, no MRSA, G-: HENPEK
28
3rd gen Cephalosporins
``` Ceftriaxone Ceftazidime* Cefoperazone* Cefixime Cefdinir Cefpodoxime Ceftibuten * Pseudomonas ```
29
3rd gen cephalos spectrum
Steph, strep, no entero, less than 1st or 2nd gen (G+), G-: HENPEK + Serratia, Citrobacter, Acinetobacter, Morganella, Providencia
30
4th generation Cephalosporin
Cefepime (broadest spectrum cephalo)
31
Cefepime
4th gen cephalo | Staph, Strep, no Entero, G-: broad G-, +pseudomonas
32
5th generation Cephalosporin
Ceftaroline
33
Ceftaroline
Staph, MRSA**, Strep, Entero (minimal)
34
Cephalosporin Tox
Mostly tolerated Most common = allergy: anaphylaxis, urticaria, fever, swelling, etc. Hemolytic anema, interstitial nephritis, vasculitis Long term = myelosupression, large PO = GI tox Cefotetan, Cefmetazole, and Cefimandole = antabuse reaction, platelet dysfunction (bleeding)
35
Carbapenem Pharm
All eliminated in the urine (Imipenem: brush border dihydropeptidase to inactive metabolite) Some liver metabolism (meropenem and Doripenem) Good CSF penetration with meropenem Otherwise similar to penicillins
36
Carbapenems (drugs)
``` Imipenem/Cilastatin* Meropenem*+ Doripenem*+ Ertapenem - no pseudomonas or entero *Pseudomonas +minimal E. Faecalis ```
37
Carbapenem spectrum
Staph, Strep, no MRSA, no E faecium, no VRE | G- = broad spectrum, + pseudomonas, anaerobes
38
Carbapenem Tox
mostly tolerable Seizures (neurotox) most common = allergy (anaphylaxis, urticaria, fever, swelling)
39
Aztreonam
Monobactam metabolism via liver, and renal exclusion. CSF penetration. No IgE mediated cross-reactivity with beta-lactams except Ceftazidime.
40
Aztreonam spectrum
Similar to aminoglycosides No G+ Broad G- coverage, pseudomonas
41
Aztreonam Tox
No penicillin allergy reaction Well tolerated Hepatoxicity Allergy non-related to penicillin allergy
42
Glycopeptides
Vancomycin | Teicoplanin
43
Vancomycin/Telavancin MOA
MOA: inhibits transglycosylases preventing peptidoglycan cross linking, disrupts cell membrane resulting in loss of membrane potential Pharm: No PO, IV only. Poor penetration CSF, brain, eye, prostate, lung, etc. Almost 100% renal eliminated
44
Glycopeptide Spectrum
G+: Staph, MRSA! Strep, Entero, no VRE, Clostridium difficile NO G-
45
Glycopeptide Spectrum
G+: Staph, MRSA! Strep, Entero, no VRE, Clostridium difficile NO G-
46
Lipoglycopeptides
Telavancin | Dalbavancin
47
Glycopeptide Resistance
Alteration in peptidoglycan target
48
Glycopeptide TOX
Tissue irritation, infusion related rxn Collitis, Rare: nephrotoxicity, ototoxicity
49
Polymyxins (drugs)
Polymyxin B Polymyxin E Colistimethate (prodrug)
50
Polymyxins MOA
Cationic detergent disrupts PM
51
Polymyxins Pharm
No PO, Renally eliminated
52
Polymyxins Spectrum
Broad G-, no Proteus (slimey membrane)
53
Polymyxins Resistance
Cell wall alterations (Thickening), PM alterations (slimey), Cell envelope protection by PM.
54
Polymyxins TOX
Nephrotoxicity, Neurotoxicity
55
Cyclic lipopeptides
Daptomycin
56
Daptomycin
Cyclic lipopeptides MOA: Ca dependent insertion into PM = K+ efflux resulting in loss of membrane potential. Pharm: no PO, renal elimination
57
Daptomycin Spectrum
G+: MSSA, MRSA, Staph, Strep, Entero, VRE!!! | NO G-
58
Daptomycin resistance
Alteration to reduce binding to PM
59
Daptomycin TOX
Muscle tox - rare Rabhdomyolysis (monitor CDK)
60
Aminoglycosides MOA
Binds 30S ribosomal subunit and prevents binding of 50S, inhibiting initiation of coding or miscoding effecting translocation.
61
Aminoglycoside pharm
Hexose ring, streptidine - streptomycin more active in alkaline environments Post-antibiotic effect! (bacteriocidal even under MIC) O2 dependent No PO, hydrophilic, poor penetration: CSF, brain, eye, prostate, lung, etc. Eliminated via urine
62
Aminoglycoside Agents
``` Streptomycin Gentamicin Tobramycin Netilmicin Amikacin Spectinomycin ```
63
Aminoglycoside Spectrum
G+ = minimal staph, synergy with beta-lactams and vanco against strep, staph, and entero, synergy against listeria (thick CW no PM penetration to get to ribosome) G-: broad coverage, pseudomonas Atypical: Nocardia, tuberculosis, Neisseria
64
Aminoglycoside Resistance
Modifying enzyme inactivation, reduced permeability, altered ribosome to prevent binding 1,2,3 acetyltransferase 4 phosphotransferase 5 adenylyltransferase *Amikacin is resistant to modification at 2, 3, 4, 5 (only susceptible at 1 and enzyme that modifies is less common)
65
Aminoglycoside TOX
Hypersensitivity (rare) - except topical neomycin Nephrotoxicity Ototoxicity - auditory and vestibular (balance loss) At high dose: neuromuscular blockade
66
Tetracycline MOA
Binds to 30S ribosomal subunit with inhibits protein synthesis (similar to aminoglycosides)
67
Tetracycline pharm
well absorbed PO, short half-life, PM permeable, penetrate most tissues well
68
Tetracycline drugs
Tetracycline Doxycycline Minocycline Demeclocycline
69
Tetracycline Spectrum
Strep, Staph, NO entero, Listeria, Neisseria, Moraxella, Hemophilus, Atypical: Legionella, mycoplasma, chlamydia, Rickettsia
70
Tigecycline
Glycylcycline G+: Strep, Staph, Entero, VRE, Listeria G-: broad coverage, except the 3 P's: Pseudomonas, Proteus, Providencia Atypicals: Legionella, Mycoplasma, chlamydia, Rickettsia
71
Tetracycline Resistance
Altered permeability, Altered ribosomal binding, Enzymatic inactivation of tetracycline
72
Tetracycline TOX
rare hypersensitivity, GI tox, tetra teeth, bone deformities (kids), hepatoxicity, nephrotoxicity, photosensitivity, vestibular tox (NR), tissue injury (IV infusion)
73
Chloramphenicol
MOA: Different! Reversibly binds the 50S subunit of the 70S ribosome inhibiting protein synthesis Pharm: absorbed PO, high levels orally lipophilic does not solublize well. Metabolized by liver, no renal. Penetrates CSF well
74
Chloramphenicol Spectrum
Broad G+, poor staph coverage, broad G- poor pseudomonas coverage, anaerobes, atypicals: rickettsia
75
Chloramphenicol Resistance
Alterations in PM permeability, Enzymatic inactivation of drug - chloramphenicol acetyltranferase
76
Chloramphenicol Tox
A LOT GI, Hematologic**, myelosuppression, aplastic anemia (irreversible and idosyncratic) Gray syndrome (neonates can not glucuronidate drug) Optic neuritis: visual issues both reversible and irreversible.
77
Macrolides
MOA: lipophilic = good penetration but no IV formula binds the 23S ribosomal subunit on 50S ribosome inhibiting protein synthesis Pharm: water insoluble, Erythromicin is acid labile (unstable in stomach acid). Crosses BBB
78
Macrolides drugs
Erythromycin Azithromycin Clarithromycin Dirithromycin
79
Macrolide spectrum
G+: strep, staph, no VRE, Listeria, some MRSA G-: Morexella, Hemophilus Atypical: mycoplasma, legionella, chlamydia, rickettsia, syphilis Strep/staph: Clarithro>erythro>azithro
80
Macrolide Resistance
Alteration of the ribosome (methylation of RNA target) Efflux pumps Enzymatic inactivation of drug
81
Macrolide Tox
Hypersensitivity - uncommon GI** Hepatotoxicity = ^^ liver metabolites
82
Ketolides
Semi-synthetic 14-member macrolides Increased stability to acid Similar spectrum to macrolides Similar macrolide tox - higher hepatotoxicity
83
Lincosamides
Clindamycin | MOA: bind the 50S subunit of the 70S ribosome inhibits protein synthesis
84
Clindamycin Pharm
Well absorbed PO, poor CSF/brain penetration, metabolized by the liver* (= hepatotox)
85
Clindamycin spectrum
G+: Strep, staph, no entero | Anaerobes
86
Clindamycin Resistance
Enzymatic inactivation of the drug | Alteration of the ribosome (mutation of receptor site or methylation of the ribosome to prevent drug binding)
87
Clindamycin Tox
Hypersensitivity (not adverse) GI Hepatotoxicity myelosuppression (chronic use) neutropenia
88
Oxazolidinones
Linezolid
89
Linezolid
Oxazolidinone MOA: inhibits protein synthesis by binding 23S subunit Pharm: well absorbed PO, hepatic metabolism, almost 100% BA
90
Linezolid spectrum
MSSA, MRSA, coagulase (-) staph, strep, entero, VRE | NO G-
91
Linezolid Resistance
Mutation in 23S binding site
92
Linezolid Tox
myelosuppression (reversible), optic neuritis, peripheral neuropathy (Irreversible), lactic acidosis (mitochondrial tox)
93
Protein synthesis inhibitors
Aminoglycosides: Streptomycin, Gentamicin, Tobramycin, Netilmicin, Neomycin, Amikacin, Spectinomycin Tetracyclines: Tetracycline, Doxycycline, Minocycline, Demeclocycline Glycylcyclines: Tigecycline Chloramphenicol Macrolides: Erythromycin, Azithromycin, Clarithromycin, Dirithromycin Ketolides Lincosamides: Clindamycin Oxazolidinones: Linezolid
94
30S binding - protein synth inhibitors
Aminoglycosides | Tetracyclines
95
50S binding - protein synth inhibitors
Chloramphenicol | Lincosamides
96
23S binding - protein synth inhibitors
Macrolides ketolides Oxazolidinones
97
23S binding - protein synth inhibitors
Macrolides ketolides Oxazolidinones
98
Sulfonamides
MOA: inhibit the conversion of PABA to dihydrofolic acid by inhibiting the enzyme dihydropteroate synthase Pharm: Well absorbed orally, highly lipophilic. Penetrates tissues well including brain and CSF Acetylated and glucuronidated in the liver (increased water solubility) then excreted in urine
99
Sulfonamides drugs
``` Sulfacytine Sulfisoxazole Sulfamethizole Sulfadiazine* Sulfamethoxazole* (SMX) Sulfapyridine Sulfadoxine ```
100
Pyrimidines (Sulfonamides)
Trimethoprim
101
Trimethoprim (TMP)
Inhibits conversion from dihydrofolic acid to trihydrofolic acid via enzyme dihydrofolate reductase Synergistic effect with sulfonamides -- they inhibit PABA conversion via different MOA
102
Sulfonamide Resistance
Altered enzymes Overproduction of PABA (overcome inhibition) Alteration in permeability
103
Sulfonamide TOX
Hypersensitivity (2nd most common) Photosensitivity, Nephrotox: allergic nephritis, Precipitation in urine (hematuria, crystalluria, renal damage), anemia (hemolytic, aplastic), Kernicterus, GI, Hepatotox
104
TMP/SMX spectrum
G+: minimal strep, staph, some MRSA, Listeria, no Entero G-: Nieserria, morexella, hemophilus, E coli, Klebsiella, Stenotrophomonas maltophilia, Yersinia, F tularensis, Brucella Atypical: PCP, Nocardia *Niche or uncommon pathogens
105
Trimethoprim resistance
Alterations in permeability, overproduction of dihydrofolate reductase, alterations in dihydrofolate reductase
106
TMP/SMX tox
Same as sulfonamide tox except more anemia, including megaloblastic
107
Fluoroquinolones
MOA: effects topoisomerase I and II, inhibit nicking and closing activity Pharm: absorbed PO, absorption decreased when given with cations (Ca, Mg, Fe, Cu, etc) penetrates well
108
Fluoroquinolones
MOA: effects topoisomerase I and II, inhibit nicking and closing activity Pharm: absorbed PO, absorption decreased when given with cations (Ca, Mg, Fe, Cu, etc) penetrates well
109
Fluoroquinolones (drugs)
``` Ciprofloxacin Gatifloxacin Gemifloxacin Levofloxacin Moxifloxacin Norfloxacin Ofloxacin Lomefloxacin ```
110
Fluoroquinolones spectrum
G+: staph, strep, no entero (except Cipro) G-: good coverage, +pseudomonas Anaerobic in Gati and Moxi only Atypical: mycoplasma, legionella, chlamydia, mycobacterium
111
Fluoroquinolone Resistance
Altered DNA gyrase target | Efflux pump or reduced PM permeability
112
Fluoroquinolone Tox
Hypersensitivity, GI, CNS tox (more in elderly), hepatox (uncommon), alterations in glucose (Gatifloxacin), QTc prolongation, tendon rupture (athletes), arthropathy
113
Sulfonamides drugs
``` Sulfacytine Sulfisoxazole Sulfamethizole Sulfadiazine* Sulfamethoxazole* (SMX) Sulfapyridine Sulfadoxine ```
114
Fluoroquinolones (drugs)
``` Ciprofloxacin Gatifloxacin Gemifloxacin Levofloxacin Moxifloxacin Norfloxacin Ofloxacin Lomefloxacin ```
115
Nucleic Acid Inhibitors
Sulfonamides: Sulfacytine, Sulfisoxazole, Sulfamethizole, Sulfadiazine*, Sulfamethoxazole* (SMX), Sulfapyridine, Sulfadoxine Trimethoprim Fluoroquinolones: Ciprofloxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Moxifloxacin, Norfloxacin, Ofloxacin, Lomefloxacin
116
Anti-Fungals
Polyenes: Amphotericin B, Nystatin (not systemic) Flucytosine Azoles: Fluconazole, Itraconazole, Voriconazole, Posaconazole Echinocandins: Capsofungin, Micafungin, Anidulafungin Griseofulvin Terbinafine Tolnaftate Saturated Solution of Potassium Iodide (SSKI)
117
Polyenes MOA
Bind ergosterol in fungal PM. A potassium channel is formed causing an efflux of K and loss of PM potential Ergosterol is inhibited (PM instability)
118
Polyenes Pharm
Not absorbed well PO, and insoluble in water. Must be complexed in colloidal suspension with bile acid salt to make water soluble for IV use. Hepatic and renal elimination Penetrates tissues well, concentrates in liver, spleen and kidney Long 1/2 life, once/day dose (can accumulate in bone)
119
Amphotericin B agents/spectrum
Liposomal and lipid complex Amph. B have decreases nephrotoxicity and side effects. Spec: Candida (minus lusitaniae), Aspergillus, Histoplasma, Blastomyces, Coccidioides, Zygomycetes
120
Lipid Amphotericin B
Lower toxicity, but less evidence *Used in patient that won't tolerate regular Amph-B, or those at high risk for adverse events (renal compromised patients!!)
121
Amph-B resistance
Impaired Ergosterol binding: | decreasing ergosterol in PM or altered ergosterol target
122
Amph-B tox
**Nephrotoxicity! (long term use)-- electrolyte wasting (K and Mg need to supplement) and bicarbonate wasting Need to monitor renal fxn and electrolytes Renal vasospasm: ischemia, decrease GFR and increased creatinine (duration and dose dependent, reversible) Infusion reactions Anemia
123
Nystatin
Polyene | Very high nephrotoxicity, only use PO and topical, not systemic
124
Flucytosine MOA
MOA: converted to 5-FU, and then FdUMP and FUTP which inhibit DNA and RNA synthesis respectively
125
Flucytosine Pharm
absorbed PO, renal elimination, penetrate tissue well CSF/brain
126
Flucytosine Spectrum
Cryptococcus neoformans | Candida (not often used)
127
Flucytosine Resistance
Can develop quickly-- often used with other anti-fungal drugs Altered metabolism of flucytosine (must become triphosphorylated)
128
Azoles MOA
imidazoles have only 2 N groups, triazoles have 3 N groups Imidazoles are less fungal selective and cause more tox Triazoles are more selective with less tox Azole work by inhibiting lanosterol 14-a-demethylase = decreases ergosterol synthesis Decreased ergosterol = unstable PM *decreases efficacy of Amph-B
129
Azole Pharm
Triazoles have greater affinity for fungal cells than mammalian cells = less tox Drug intxns! - induction or inhibition of drug metabolism thru CYP450 enzymes
130
Azole drugs
Fluconazole Itraconazole Voriconazole Posaconazole
131
Azole drugs
Fluconazole Itraconazole Voriconazole Posaconazole
132
Fluconazole
Azole anti-fungal IV and PO Hepatic metabolism, renal elimination (only 10% is metabolites, 90% unchanged drug in kidney BAD, requires adjustment in renally compromised patients) Penetrate CSF/tissues USE: Dermatophytes, cryptococosis, candidiasis, coccidiodes Tox: GI, hepatotox, alopecia*
133
Itraconazole
Azole anti-fungal IV and PO *decreased oral absorption with increased stomach pH - don't use PPI's or antacids before use metabolized in liver good tissue/CSF penetration USE: dermophytes, onychomycosis, blastomycosis, histoplasmosis Tox: GI, Hepatotox, mineral corticoid excess*, negative inotropy* (low EF and heart fxn, can increase BP with fluids)
134
Voriconazole
Azole anti-fungal IV and PO Long 1/2 life Metabolized hepatically penetrate tissue/CSF well USE: aspergillus, candidiasis, blastomycosis, histoplasmosis TOX: GI, hepatotox, visual changes* (rule of 30s), photosensitivity*
135
Posaconazole
``` azole anti-fungal PO only liver metabolized penetrates well USE: "BAD molds": aspergillus, candidiasis, blastomycosis, histoplasmosis, zygomycectes TOX: no significant, GI, and hepatotox ```
136
Posaconazole
``` azole anti-fungal PO only liver metabolized penetrates well USE: "BAD molds": aspergillus, candidiasis, blastomycosis, histoplasmosis, zygomycectes TOX: no significant, GI, and hepatotox ```
137
Azole resistance
Increased efflux of azole Over expression of lanosterol 14-a-demethylase (overcomes inhibition of ergosterol synthesis) point mutation leading to decreases affinity of azoles for lanosterol
138
Echinocandin MOA
inhibit beta-glucan synthase preventing synthesis of beta-glucan resulting in weak cell wall and structural instability
139
Echinocandin pharm
Not absorbed orally, IV only (large cyclic peptides) metabolized in situ Hepatic metabolism (capsofungin and Micafungin)
140
Echinocandin Spectrum
Candidas and Aspergillus ONLY | minus C. parapsilosis due to high MIC required
141
Echinocandin Resistance
Mutation at Beta-(1,3)-glucan preventing synth inhibition | Up-regulation of chitin synthesis, makes up for beta-glucan loss.
142
Echinocandin Tox
Histamine release during infusion hypersensitivity hypokalemia hepatotoxicity (increase ALT/AST with cyclosporines)
143
Echinocandin drugs
Capsofungin Micafungin Anidulafungin
144
Griseofulvin
anti-fungal MOA: inhibits fungal mitosis by binding microtubules disrupting mitotic spindle binds keratin precursor cells, preventing new nails from infection Tox: GI, (not as used due to replacement therapy)
145
Terbinafine
Anti-fungal MOA: Allylamine inhibits ergosterol synthesis (enzyme squalene epoxidase) Topical and oral only Use: skin/nail infections, athletes foot/ skin-skin infections Tox: hepatitis, and hepatotoxicity
146
Tolnaftate
Anti-fungal MOA: thiocarbamate, topical USE: limited spectrum, Tinea infections -don't need to know much
147
Saturated Solution of Potassium Iodide (SSKI)
Anti-fungal Oral solution TOX: nausea, bitter emesis, hypersalivation USE: former treatment of Sporotrichosis (now itraconazole)
148
Anti-Herpes agents
``` Acyclovir Valacyclovir Famciclovir Penciclovir Docosanol Trifluridine ```
149
Anti-herpes agents MOA
*Must be triphosporylated to work (to look like NTPs) Acyclovir and Penciclovir require all 3 phosphorylations, first by virus-specific enzymes, thymidine kinase, (point of resistance) and the 2nd and 3rd phosphorylation are by mammalian enzymes Trifluridine, cidofovir, and foscarnet already have 1st phosphate, so they can bypass the viral kinase step directly phophorylated by mammalian kinases. After activation, drug is either directly bound to DNA polymerase to prevent replication or incorporated into DNA resulting in early termination.
150
Acyclovir
``` Anti-herpes Acyclic guanosine derivative HSV-1 HSV-2 and VZV MOA: requires 3 phosphorylations, prevents or terminates DNA synthesis IV and PO Renal elimination, minimal hepatic Penetrates most tissues ```
151
Acyclovir Resistance
Alteration of thymidine kinase | Alteration in DNA polymerase
152
Acyclovir TOX
GI nephrotox - must be renally adjusted Neurotox - tremors, delirium, seizures, AMS
153
Famciclovir
``` Anti-herpes Prodrug of penciclovir Hepatically metabolized HSV-1 HSV-2 and VZV MOA: requires 3 phosphorylation to inhibit DNA synthesis ```
154
Famciclovir Resistance
Alteration in thymidine Kinase
155
Famciclovir TOX
GI, less nephro- and neurotox | concentration dependent
156
Valacyclovir
Anti-herpes Prodrug of acyclovir - hydrolyzed to acyclovir in liver/intestine improved PO absorbance Same resistance/tox as acyclovir
157
Penciclovir
Anti-herpes agent Active metabolite of famciclovir Topical only treatment of oral herpes
158
Docosanol
``` Anti-herpes agent USE: HSV-1 and HSV-2 MOA: inhibits fusion of PM and viral envelope Topical Tox: minimal ```
159
Trifluridine
Fluorinated pyrimidine nucleoside Use: HSV-1, HSV-2, CMV MOA: phosphorylated intracellularly by host enzymes, then competes with thymidine triphosphate for incorporation by viral DNA polymerase
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Cytomegalovirus agents
Ganciclovir Valganciclovir Foscarnet Cidofovir
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Cytomegalovirus agents MOA
Same as anti-herpes agents Ganciclovir needs all 3 phosphorylations, relies on protein kinase phosphotransferase (UL97). Cidofovir and Foscarnet come with 1 phosphate group, do not rely on thimidine kinase and are directly phosphorylated by host enzymes
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Ganciclovir
``` CMV agent acyclic guanosine derivative Use: CMV, HSV1, HSV2 and VZV MOA: requires 3 phosphorylations to be active and inhibit DNA synthesis (protein kinase UL97) IV and PO, poor oral absorption Renally eliminated Penetrates most tissues ```
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Ganciclovir Resistance
Alterations in protein kinase (UL97) | Alteration in DNA polymerase (UL54)
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Ganciclovir TOX
``` GI myelosuppression - leukopenia hepatotoxicity Teratogenic** Neurotox - (more without renal adjustment) ```
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Valganciclovir
CMV agent Ganciclovir plus valine group (improved BA) acyclic guanosine derivative USE: CMV, HSV1, HSV2, VZV 100x more active against CMV than acyclovir MOA: Requires 3 phosphorylation steps to be active 1st phosphate group added by protein kinase phosphotransferase UL97 Only PO renally eliminated Penetrates most tissue - no CNS
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Valganciclovir Resistance
Alteration of UL97 | Alteration in DNA polymerase (UL54)
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Valganciclovir TOX
``` GI Myelosuppression hepatotox teratogenic neurotox Same as ganciclocvir ```
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Foscarnet
``` CMV agent MOA: does not require viral enzyme for 1st phosphorylation, inhibits DNA polymerase, RNA polymerase, HIV reverse transcriptase Use: HSV1, HSV2, VZV, CMV, EBV, HIV-1 IV only penetrate +CNS Renal elimination ```
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Foscarnet Resistance
Point mutation in DNA polymerase and HIV reverse transcriptase
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Foscarnet Tox
``` Nephrotox - serum creatinine and must monitor electrolytes Electrolyte disturbances GI Hepatotox CNS Infusion arrhythmias, numbness, tingling ```
171
Cidofovir
CMV agent HIGHLY NEPHROTOXIC acyclic cytosine analog MOA: does not require first phosphorylation, independent of protein kinase. Inhibits DNA polymerase, or incorporated into DNA. Use: CMV, HSV1, HSV2, VZV, EBV, polyomavirus Poor CNS penetration Renally eliminated
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Cidofovir Resistance
Point mutation in DNA polymerase (no UL97) *Cidofovir resistance isolates are usually also resistant to ganciclovir, but susceptible to foscarnet Cidofovir resistance predicts foscarnet resistance but not the other way around!
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Cidofovir Tox
Nephrotox!! Ocular tox neutropenia Mutagenic, gonadotoxic, and embryotoxic (infertility)
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NRTI drugs
``` HIV agents Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine ```
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NNRTI drugs
``` HIV agents Nevirapine Delavirdine Efavirenz Etravirine Rilpivirine ```
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NRTIs
Looks like nucleoside/nucleotides Need to be triphosphorylated to be active Same as guanaline analogs = early termination or direct inhibition of enzymes
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NRTIs
Looks like nucleoside/nucleotides Need to be triphosphorylated to be active Same as guanaline analogs = early termination or direct inhibition of enzymes MOA: competitive inhibition of HIV-1 reverse transcriptase, incorporation into growing viral DNA chain = termination Hepatic and renal elimination
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NRTIs TOX
Mitochondrial tox (inhibits mitochondrial DNA polymerase gamma), lactic acidosis, hepatotoxicity
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NNRTIs
Bind directly to HIV-1 reverse transcriptase, DO NOT require phosphorylation Hepatically metabolized
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NNRTI tox
GI, skin rash | Liver enzyme induced drug interactions! CYP450
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Protease Inhibitors
``` Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir/ritonavir Nelfinavir Ritonavir Saquinavir Tipranavir ```
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Protease Inhibitor MOA
Prevents post-translational cleavage of the Gag-Pol polyprotein = prevents processing of viral proteins into functional conformations, or results in production of immature/non-infectious particles Do not require intracellular activation Hepatic metabolism
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Protease Inhibitor Tox
``` Redistribution of body fat - peripheral and facial fat wasting, central obesity, buffalo hump, breast enlargement Hyperlipidemia Hyperglycemia, diabetes Osteoporosis Live enzyme drug interactions, CYP450 ```
184
Entry inhibitors
HIV agent CCR5 Antagonist: Maraviroc Fusion inhibitor: Enfuvirtide
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Maraviroc MOA
Binds CCR5 entry of CCR5 tropic HIV Co-receptors are necessary for the entrance of HIV into CD4 cells: CCR5 CXCR4 HIV has 2 receptors, one of each, or both or one or the other **Only active against CCR5 + CCR5 HIV Hepatically metabolized Not 1st line, only for resistance HIV with CCR5/CCR5 receptors
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Maraviroc Resistance
Mutation in CCR5 receptor | Presence of non-CCR5 tropic HIV
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Maraviroc TOX
``` Cough Respiratory problems Muscle/joint pain Diarrhea Sleep disturbances** Hepatotox ```
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Enfuvirtide
MOA: inhibits HIV entry into cell by binding gp41 metabolized via proteolytic hydrolysis Resistance: mutations in gp41 codon, no cross-resistance TOX: injection site reactions, hypersensitivity
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Intergrase Inhibitor
Raltegravir Dolutegravir Elvitegravir
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Intergrase Inhibitors
HIV agents Pyrimidinone analog MOA: binds intergrase which inhibits strand transfer thus interfering with integration of reverse transcribed viral DNA into the chromosome of the host cell Drug is glucuronidated, liver metabolism but not CYP450. Glucuronidated = increased water solubility.
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Intergrase Inhibitors
HIV agents Pyrimidinone analog MOA: binds intergrase which inhibits strand transfer thus interfering with integration of reverse transcribed viral DNA into the chromosome of the host cell Drug is glucuronidated, liver metabolism but not CYP450. Glucuronidated = increased water solubility.
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Intergrase Inhibitors Resistance
Mutations in intergrase
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Intergrase Inhibitors Resistance
Mutations in intergrase
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1st line Anti-mycobacterials
``` Isoniazid Rifampin Ethambutol Pyrazinamide Streptomycin ```
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2nd line Anti-mycobacterials
``` Amikacin Aminosalicylic Acid Capreomycin Ciprofloxacin Clofazamine Cycloserine Ethionamide Levofloxacin Rifabutin Rifapentine ```
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Isoniazid
``` Anti-mycobacterial Prodrug MOA: most active against M tuberculosis. Inhibits the synthesis of mycolic acid Bactericidal Hepatically metabolized ```
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Isoniazid Resistance
Point mutations in katG (low level - effective at higher doses) Large mutation or deletion in katG (high level - no efficacy) Mutations in inhA (low level resistance)
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Isoniazid Toxicity
Hepatotox** significant drug interactions, minor increases in liver enzymes, hepatitis/liver failure Neurotox - peripheral neuropathy due to clearance of pyridoxine (usually supplemented) Hypersensitivity rxn
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Isoniazid OD
Large doses = metabolic acidosis, hyperglycemia, Seizures**, coma**
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Rifampin
``` Anti-mycobacterial MOA: binds to beta subunit of bacterial DNA dependent RNA polymerase and inhibits RNA synthesis Bactericidal Penetrates tissues Hepatically metabolized ```
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Rifampin Resistance
Mutations in rpoB - gene for beta subunit of RNA polymerase.
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Rifampin TOX
Hepatotox - hepatitis, drug interactions*, failure (fatal) Nephrotox - nephritis, acute tubular necrosis (rare) Hypersensitivity Orange body fluid discoloration Flu-like symptoms - more common with high dose/intermittent therapy
203
Ethambutol
Anti-mycobacterial MOA: inhibits arabinosyl transferase enzyme involved in arabinogalactan biosynthesis within cell wall, = instability *bacteriostatic Hepatically metabolized
204
Ethambutol Resistance
The embCAB operon codes for synthesis of arabinogalactan and lipoarabinogalactan (overcomes inhibition of enzymes) Mutations in emb = loss of ethambutol activity
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Ethambutol TOX
``` Optic Neuritis (larger doses) Hypersensitivity rxn ```
206
Pyrazinamide
Anti-microbacterial MOA: synthetic analog of nicotinamide. prodrug- must be converted to pyrazanoic acid to be active. MOA unknown Bactericidal Hepatically metabolized
207
Pyrazinamide Resistance
Mutations in pncA (codes for pyrazinamidase) = decreased activation of pyrazinamide into pyrazanoic acid = decreased concentration)
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Pyrazinamide TOX
``` Hepatotox N/V Polyarthalgias* (joint pain) Nephrotoxicity Hypersensitivity Urate retention (exacerbates gout) Photosensitivity ```

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