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196 Cards in this Set

  • Front
  • Back
which TB drugs affect MT cells wall?
EMB
PZA
INH
which TB drugs have no cross-resistance?
INH, RIF, EMB
which 5 drugs are first-line agents for TB treatment?
EMB
PZA
INH
RIF
SM
Which combo of drugs can cure the majority of TB cases?
INH-RIF
must give for 9 months, can cure 95-98% of cases
How can the above TB treatment be shortened?
INH-RIF-PZA for the first 2 months decreases duration of tx to 6 months
Is INH cidal or static? To MT found where?
Cidal against extracellular mycobacteria; active against intra and extracellular bacteria
MOA of INH
inhibits mycolici acid synthesis
it is in a prodrug form that is activated by KatG catalase-peroxidase
inhibits InhA and KasA (subunits of FASII) that converts unsat --> sat mycolic acid
how does resistance develop to INH?
mutations in InhA, KasA, KatG
What other organisms are killed by INH?
none, mycolic acid is unique to mycobacteria
Most common adverse rxns to INH
fever
skin rash
hepatitis (fatal if pt is >50 yo)
peripheral neuropathy (reversed by B6)
MOA of PZA
sim to INH
is a prodrug activated by PcnA
Targets FASI (responsible for de novo FA synthesis)
is PZA cidal or static?
Cidal (even in dormant bacteria)
How does resistance occur against PZA?
quickly acquires mutations in PcnA
What does PZA work in synergy with?
INH and RIF
Adverse effects of PZA?
hepatotoxicity
n/v
drug fever
hyperuricemia
Is EMB cidal or static?
static
MOA of EMB?
blocks incorporation of arabinose into arabinogalactan, weakening the cell wall
Inhibits arabinosyl transferase
what encodes for arabinosyl transferase?
embA and embB
Adverse effects of EMB
optic neuritis and r-g color blindness
MOA of RIF
broad spectrum AB against gram - and +, mycobacteria, and chlamydia
Blocks departure of bacterial RNA polymerase (RNAP) from gene promoteres
Prevents RNA from exiting the polymerase by interacting with the beta subunit of bacterial RNAP
Is RIF cidal or static in TB?
cidal against fast growing extraellular MT in lung and also effective against slow growing intracellular organisms
What can RIF be combined with to treat leprosy or atypical mycobacterial infection?
RIF + sulfone
What can RIF be combined with to treat meningitis?
RIF + Ceftiraxone/Vanco
Adverse effects fo RIF?
flu like sx (if given <2x weekly)
increased elimination of other drugs (induced p450)
Orange color to urine, sweat, and tears (harmless)
rash, thrombocytopenia, nephritis, hepatitis)
When is SM used in TB?
to tx life-threatening TB forms (eg meningitis) and drug resistant bacteria
Disadvantages of SM in TB?
doesn't enter CNS or macrophages
rapidly arising mutations
otoxoicity, nephrotoxicity
When to use 2nd line TB drugs?
when R to 1st line drugs emerges
failure to respond to tx
What is capreomycin? MOA?
2nd line Tb tx
MOA similar to SM
MOA of Ethionamide?
cidal or static?
blocks mycolic acid synth
mycobcterial monooxygenase converts drug into reactive intermediate that resembles activated INH
static
Adverse effects of ethionamide?
gastric irritation
neuro sx
Adverse effects of Cycloserine
Peripheral neuropathy
CNS dysfxn
give with B6 to reduce neurotoxicity
MOA of PAS
derivative of PABA
works like sulfonamies (anti-folate drug, blocks nucleic acid synth)
Adverse effects of PAS
GI distress
hypersensitivity (rash, joint pain, fever)
What % of mycobacterial infections are from non-TB species?
How is it treated?
10%
combo of drugs
What causes leprosy?
treatment?
M. leprae
Dapsone, RIF, clofazimine
MOA of Dapsone
inhibits folate synth
well absorbed and distributed, [] in infected skin
adverse effects of dapsone
hemolysis (in G6PD deficiency)
methemoglobinemia
fever
pruritis
rash
MOA of clofazimine
unknown
adverse effects of clofazimine
[] in skin and reticuloendothelial cells
What are most UTI caused by?
E coli, Staph saprophyticus, Proteus marabilis, K. pneumonia, Enterococcus faecalis
Examples of sulfonamides
Sulfamethoxazole
Sufacytine
Sulfisoxazole
Sulfamethizole
Sulfadiazin
Sulfapyridien
Sulfadoxine
What drugs are related to sulfonamides?
dapsone
PAS
What are examples of folate reductase inhibitors?
trimethoprim
pyrimethamine
Ex of DNA gyrase inhibitors
Quinolones
Fluoroquinolones
(nalidixic acid, ciproflxacin, sparfloxacin, norfloxacin, moxafloxacin)
What are sulfonamides structurally related to?
PABA (inhibits biochem pathways taht require PABA, such as DNA synth)
What pH are sulfonamides least soluble at? what are the implications of this?
low pH = low solubility
precipitates in the urine --> kidney damage
which sulfonamides are most soluble?
sulfisoxazole and sulfamethoxazole
MOA of sulfonamides
inhibits PABA formation in bacteria (humans don't make this, so doesn't affect them)
Inhibits PABA pathways
How do bacteria become resistant to sulfonamides?
overproduction of PABA
dihydropteroate synthase with low affinity to sulfonamides can be transmitted in plasmid
Clinical uses of sulfonamides
UTIs
What is the spectrum of bacteria sulfonamides are effective against?
gram + and gram - bacteria
nocardia
chlamydia
some protozoa
also for URI as a B-lactam alt
can be a compoonent of malaria tx
are sulfonamides cidal or static
static
what do sulfonamides do to rickettsiae?
stimulate their growth
What is the t1/2 of sulfamethoxazole
absorption?
daily dosage?
10-12 hrs
slow
1g x 2-3
adverse rxns to sulfonamides
hypersensitivity
Stevens Johnson syndroem
stomatitis
conjunctivitis
arthritis
hepatitis
precipitation in kidney
hemolytic anemia (in G6PD defic), granulocytopenia, thrombocytopenia
what are sulfonamides NOT effective against?
Proteus
Serratia
Pseudomonas
how do sulfonamides affect pregnant women?
if taken in end of preg, can increae the risk of kernicterus in newborns by interfering with bilirubin met
How do folate inhibitors work?
inhibit tetrahydrofolic acid synthesis by inhibiting thymidylate synthetase (blocks dUMP --> dTMP) so can't --> DNA
how does resistance arise to folate inhibitors?
reduced cell permeability to the drugs
overproduction of DHFR or drug-resistant DHFR passed on in plasmid or transposon
How is trimethoprim administered?
orally, absorbed through gut, good tissue penetration (even in CNS)
t 1/2 of trimethoprim
10-12 hrs
what can trimethoprim be combined with to make it bacteriacidal?
sulfonamides
adverse effects of TMP (trimethoprim)
anemia
leukopenia
granulocytopenia
(all only a prob when used chronically)
Abbreviation for sulfonamides?
SMX
describe co-administration of SMX and TMP?
TMP inhibits dihydrofolate reducatase (so no formation of dihydrofolic acid) and SMX inhibits dihydropteroate synthase which prevents DHF --> MTHF (also needed for formation of dTMP from dUMP required for DNa synth)
Which drugs are the DNA gyrase inhibitors?
quinolones
fluorquinolones
advantages of fluoroquinolones?
good oral absorption
broad spectrum (G+/- and mycobacteria)
cidal
good tissue distribution
mild side effects
new drug, so little resistance
MOA of fluorquinolones in Gm + and -
inhibit bacterial gyrase (gram - target) and topo IV (gram + target)
R against fluoroquinolones
mutations in target enzyme, decreasing binding of drugs
lower perm of cell wall to drugs
R develops to ALL quinolones
Spectrum of 1st generation fluoroquinolones
Gm - (enterobacteraceae, psduomonas, neisseria, haemophilus, campylobacter)
Staph, strep (incl MRSA)
anthrax
no effect on anaerobes
spectrum of 2nd generation fluorquinolones
gm +/-
atypical pneumonias (mycoplasma, chlamydia)
intracellular pathogens (legionella, some mycobacteria, incl MT and M. avium)
some anaerobes
NOT effective against Enterococcus faecalis
What do ciprofloxacin and ofloxacin treat?
gonococcal infections
ofloxacin treats?
chlamydial urethritis or cervicitis and gonorrhea
Ciprofloxacin treats?
2nd line agent for legionellosis and gonorrhea
Cipro + levofloxacin treat?
TB and atypical mycobacterail infections
What are fluorquinolones NOT receommended for?
pneumonia or URTI
adverse effects to all florquinolones
diarrhea
N/V
damage growing cartilage and cause reversible arthropathy
dont' give to children under 18 or pregnant women
tendonitis and increased risk of tendon rupture
adverse rxn to trovafloxacin
acute hepatitis
hepatic failure
advesre rxn to lomefloxacin and perfloxacin
photosensitivity
which fluorquinolones --> QT prolongation?
sparfloxacin
gatifloxacin
levofloxacin
moxifloxacin
Adverse effects of gatifloxacin?
hyperglycemia in diabetics
hypoglycemia in pts receiving hypoglycemic agents
What is the vector for malaria
What is the organism that most commonly causes malaria
Anopheles mosquito
Plasmodium vivax
How many deaths/year from malaria
3 million (mostly children)
What is the life-cycle of plasmodium falciparum, starting with mosquito bite
Sporozoite in saliva of mosquito, merozoite in hepatocyte and invade RBC, schizonts in RBC, gametocytes taken up by mosquito, become oocyte and enters gut wall
How much of total RBC protein is Hb
How much Hb is degraded by parasite
95%
60-80%
What is the severity and cycle of P. vivax malaria?
benign,
tertian (days 1 &3)
relapsing
what is characteristic cycle?
What is meant by relapsign
cycle fo chills, fevers that occurs when parasites burst from RBC

organisms persist in liver as hypnozoites adn can reinfect RB to produce repeated dz even after RBC infection has been cured
What is severity and cycle fo P. falciparum malaria?
malignant
tertian (days 1 &3)
not relapsing
What is severity and cycle of P. malariae
benign
quartian (days 1 &4)
not relapsing
What is severity and cycle of P. ovale
benign
tertian
relapsing
What is goal of pharmacological proph for malaria?
kill sporozoites before primary liver schizonts and RBC are involved
Where is chloroquine effective proph?
dominican republic
haiti
central america W of panama Canal
Egypt
Middle East
Which drugs should travelers to Africa, India, and Asia take for proph
mefloquine
Doxycycline
malarone
What is malarone a combo of?
atovaquone + proguanil
Uses for mefloquine
proph for a short stay
treats drug-resistnat strains at high doses (w increased side effects )
MOA of mefloquine
unknown
Pharmacodynamics of mefloquine (MEF)
effects of food
frequency of dosing
distrubution
orally, food aids absorption
take 1 week before arrival, then once a week, and 4 weeks after return
wide distribution
t 1/2 20 days
toxicity of mefloquine
teratogenic at high doses
single dose can kill child
can't disting toxicity from clinical illness
neuropsych distrubances (stop at once!)
n/V/abdominal pain, diarrhea, dysphoria, dizziness
contraindication of MEF
pts with cardiac conduction abnormalities
Alternatives to MEF in resistnat areas
Doxy and malarone
Uses of Doxy
used alone as proph
can be used with quinine for tx
pharmacodynamics of doxy
dosing for malaria proph
oral daily dose one day before travel
continue during travel and four week safter
take w food
MOA of doxy
DOX inhibits 30S subunit for protein synth
Toxicities of DOX
not given to pregnant women or children uner 8 d/t adverse effcts on bone and teeth
photosensitivity
nausea
vaginal yeast super-infections
other tetracycline side efefcts
What is malarone a combo of
atovaquone
proguanil
use of Malarone
alternative to MEF and DOX for proph
1st line proph drug in areas with MEF or chloroquine resitance P. falciparum malaria
What can Malarone be used with
primaquine against relapsing malarial infection
benefit of Malarone
b/c of drug combo, there is synergistic activity that avoids emergence fo drug resistnace
Uses of Atovaquone
targets all malarial parasites
when used alone, R is quick
MOA atovaquone
collapses mitochondrial membrane potential, interfering w ATP synth
targets parasitic mitochondrian ubquinol-cytochrome c oxidoreductase
what works synergistically with atovaquone
proguanil
How does R occur against atovaquone
mutations in cytochrome bc1 (ubquinol-cytochrome c oxidoreductase)
disruption of electron transport ==> environment for oxidative DNA damage
toxicities of atovaquone
few
hard to disting from manifestation of dz
rash, fever, diarrhea, HA
MOA proguanil
proguanil is converted into cyclguanil, which activates the drug
inhibits plasmodial dihydrofolate reductase-thymidylate synthase
synergizes mito membrane dopolarization by atovaquone
Uses of proguanil
controls acute attacks and eradiates infection
MOR against proguanil
mutations in DHFR binding site
Pharmacodynamics of proguanil
speed of onset
t 1/2
metabolism
where is it concnetrated
taken orally and absorbed from GI
slow onset
20 hrs
met by p450
[] in infected RBC
toxicity of proguanil
contraindication
diarrhea, abdominal pain, vomiting
hematuria
renal impairment
Use of fansidar
fixed dose combo for proph and uppression in CQ resistant areas
What is fansidar a combination of?
sulfadoxine and pyrimethamine
MOA fansidar
affects folic acid synth in plasmodium, but not in mammals (pyrimethamine is DHFR inhibitor and sulfodoxine inhibits dihydropteroate synthase)
MOR fansidar
multiple point mutations in each of target enzymes
what can be used when there is fansidar resistance?
proguanil-dapsone (for leprosy also)
toxicity of fansidar
stevens-johnson syndrome
megalblastic anemia resembling folate defic
contraindications of fansidar
pregnancy
breast feeding
infants <24 lbs
What does dihydropteroate synthase do?
DHFR?
catalyzes rxn bewteen pteridine + PABA --> Dihydropteroic acid --> (blocked by sulfadoxine; an impt initial step in nucelic acid synth) dihydrofolic acid (DHFR... blocked by pyrimeethamine) --> THF --> nucleic acid synth
If parasite is P. vivax, P. malaria, P. ovale or CQ sensitive P. falciparum, what drug is used to cure?
CQ
Primaquine is added for radical cure, if needed
What to use if infected with CQ resistant P. falciparum w mild attack
what if attack is severe?
Malarone or oral quinine + Doxy
IV quinen + Doxy or other tetracycline)
What is CQ effective against
RBC forms fo P. vivax, P. ovale, P. malariae, P. falciparum
NOT gametocidal for P. falciparum, doesn't work on latent forms
When to suspect CQ resistance?
If no improvement by 2nd day (ie still febrile)
MOA of CQ in treating malaria
accumulates in food vacuole 1000x over host plasma
blocks heme polymerization in parasite food vacuole
MOR against CQ
mutation in pfcrt ( a vaculoar drug efflux pump)
requires 5-8 point mmutations of gene
How is Hb broken down into food for parasite
Hb --> heme + globin by parasital proteases
heme --> hemozoin (blocked by CQ, so heme reacts w vacuole membrane, contents spill, parasite death)
Globin --> peptides + AA --> plasmodia biosynth
Toxicities of CQ
CV
CNS
I upset, HA, visual disturbances, uticaria, pruritis in dark skinned
hemolysis in G6PD defic
Contraindications for CQ
epilepsy
mysthenia gravis
psoriasis
Uses of quinine
used w anti-folate drug as 1st line t of acute CQ resistnat P. falciparum
NOT Proph
MOA of quinine
acts as blood schizontocide
little effct on sporozoites but effective against gametocytes other than P. falciparum
Toxicity with quinine
more toxic adn less effective than CQ
cinchoism
hypoglycemia
hypotension
increased contractile responses and increased refractory perid before next response
--> MG sx
Contraindications for quinine use
antagonizes physostigmine on skel muscle --> respiratoyr distress
Uses of artemesinins
MOA
most rapid effective safe dru g
acts on asexual RBC stage of P. vivax adn P. falciparum
10-100x more active than other drug s
NO PROPH - t/12 too short
MOA artemesinins
unkonw, may involve maarial intracelular Ca stores
MOR artermesinins
mutations in Ca dependent AtPase of sarcomere/ER (resistance is not widespread now)
Toxicity associated with artemesinins
none
Drug to treat and cure relapsing malaria
P. ovale?
Primaquine
Primaquine
what is the benefit of primaquine
only drug to eradicate vivax and ovale latent schizonts from liver
also gametocidal
What is primaquine ineffective against
RBC stages of P. falciparum
Toxicities of primaquine
CGPD deficiencies uncovered by primaquine
methemoglobinemia and hemolytic anemai
large doses --> epigastric and abdominal distress, take at mealtime
MOA amphotericin B
why is is specific to fungus
binds to ergosterol in fungal membrane and forms pores that cause membrane leakage
selective for fungi b/c predominant sterol of human and bactereail cell membranes is cholesterol
What fungi does amphotericin B have limited activity against?
Leishmania braziliensis
Naegleria fowleri
What is the basic structure of amphotericin B?
amphoteric poyene macdrolide, insoluble in water
where is amphotericin B absorbed?
poorly absorbed by GI, so given by infusion
oral admin is only for GI infections
how is amphotericin B metabolized
>90% bound by serum proteins, metab mostly by liver
amphotericin B is excreted slowly in urine over pd of several days
serum t 1/2 of amphotericin
15 days
Clinical uses of amphotericin B
all life threatening systemic fungal infections
used as induction tx= in critical cases, followed by azoles for chronic tx or relapse prevention
empiric tx in cancer pts
intrathecal admin if nonresponsive CNS fungal infection
can cure mycotic corneal ulcers, keratiniiits, fungal arthritis, candiduria
adverse effects of amphitericin B
renal damage
infusion related toxicity (fever, chills, vomiting, HA, hypotension)
anemia from lowered EPO
occassioinal impaired liver fxn
MOA flucytosine
taken up by fungal cyctosine permease and converted to 5-FU by cytosine deaminase --> 5-FdUMP and FUTP (which inhibits DNA/RNA synth)
how is flucytosine specific to fungi?
human cells can't convert 5-FC to toxic metabolites so are not affected by drug
MOR to flucytosine (5FC)
loss of permease (so drug isn't taken up)
loss of5FC --> 5FU or 5FU --> 5FUMP conversion
how is drug administered
protein bound?
distribution
elimination?
when can levels rise quickly?
orally
poorly, so penetrates into all body fluid compartments, incl CSF
glomerular filtration, can lead to renal toxiciyt
in AIDS pts and those wiht renal insuff
whihc drug works synergistically with 5FC?
amphotericin B, b/c of beter penetration ofo flucytosine through amphotericin damaged fungal membranes
synergy w azole drugs too, but unknown MOA
Clinical uses for flucytosine
Cryptococcus neoformans, some candida species
combo with itraconazole for chromoblastomycosis
combo with amphotericin B for cryptococcal meningitis
Toxicity of 5FC
d/t conversion to 5FU by intestinal flora
bone marrow toxicity w/ anemia, leukopenia, thrombocytopenia,
rash, N/V,D, enterocolitis
Drugs that increase itraconazole
larithromycin
indavinir
ritovanir
Solubulity of fluconazole
distribution?
oral bioavail?
effect on hepatic enzymes
water sol
CSF
good
oral bioavail
least effects of all azoles, drug interaction less common
Uses of fluconazole
tx of choice in cryptococcal meningitis
equiv to amphotericin B in candidemia tx and skin candidasis
what can fluconazole not be used for?
aspergillus
filamentous fungi
Metabolism of vericonazole
hepatic, but low inhibition of mammalian p450
toxicity with vericonazole
visual disturbances
bluring change in color vision/brightness
both resolve within 30 mins
spectrum of action of vericonazole
similar to itraconazole
candida and dimorphic fungi
Structure of echinocandins
large cyclic peptides linked to long-chain FA
MOA of echinocandins
act at level of fungal cell wall by inhibiitng synth of beta(1-3) glucan --> cell death
uses of echinocandins
candida
aspergillus
NOT C. neoformans
administration of echinocandin
IV admin only
examples of echinocandins
micafungin
anidulafungin
caspofungin
Use of micofungin
mucucutaneous candidiasis and proph of candida infections in bone marrow transplant pts
use of andiulafungin
esoph candidiasis and invasive candidiasis and septicemia
use of caspofungin
disseminated and mucocutaneous candida infections
ONLY TO BE USED IF PT HAS FAILED TO RESPOND TO AMPHITERICIN B TX
adverse effects of echinocandins and drug interactions
minor GI effects and flushing
elevated liver enzymes if caspofungin + cyclosporine
micofungin --> increasd lvls of nifedipine, cyclosporine, adn sirolimus
andulafungin --> no drug interactions
Which drugs are systemic drugs used for mucocutaenous fungal infections
griseofulvin
terbenafine
MOA of griseofulvin
deposition in newly forming kin, where it binds to keratin, protecting new skin from new infections
how long can tx with griseofulvin last
several months for a nail infection
clinical uses of griseofulvin
systemic tx of dermatophytosis
largely replaced by itraconazole and terbinafine
toxicity of griseofulvin
allergic syndrome, like serum sickness
hepatitis
drug intearctions wiht griseofulvin
induces p450, speeds up metabolism of warfarin and phenobarbital
MOA terbenafine
inhibits squalene epoxidase (fungal enzyme) --> accumulation of sterol squaline (toxic to fungus)
clinical uses of terbenafine
12 weeks cures onychomycosis in 90%
more effectve than griseofulvin or itraconazole
toxicity of terbenafine
mild GI upset
HA
drug interactions with terbenafine
doesn't affect p450 system, no significant drug interactions
Structure of nystatin
polyene macrolide, too toxic for parenteral admin, so only topical use
absorption fo nystatin
not absorbe by skin , mucous membranes, or GI tract
toxicity of nystatin
little, because not absorbed
uses of nystatin
local suppression of candida species
MOA terbinafine/naftifine
uses
inhibit squalene epxidase needed to make ergosterol
dermatophytosis
adverse effects of terbinafine/naftidine
local irritation
burning
erythema
avoid contact w mucous membranes
Uses of clotrimaolz/miconazole
vulvovaginal candiasis
oral clotrimazole troches for oral thrush
tinea corporis, tinea pedis, and tinea cruris (topical)
what is used to treat seborrheic dermatitis and pityriasis versicolor?
ketoconazole shampoo