quinolones, folic acid antagonists and urinary antiseptics Flashcards
what compound was the structure of fluroquinolones derived from
nalidixic acid
draw structure of nalidixic acid
what is the infection that is most commonly associated with fluoroquinolones
c. difficile and abx resistance
what are the examples of fluoroquinolones
ciprofloxacin, levofloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin
what is the moa of fluoroquinolones
target primarily DNA gyrase in gram neg bacteria and topoisomerase IV in gram pos bacteria to inhibit DNA replication
do eukaryotic cells (human) contain DNA gyrase
no, have topoisomerase II which works mechanistically similar to DNA gyrase and will be inhibited by fluoroquinolones at high conc
what are the routes for fluoroquinolones
IV, PO, ophthalmic
what is the absorption, distribution and excretion of fluoroquinolones
well absorbed after taking orally, best on empty stomach, to take 2h before or 6h after if ingesting with potential fdi
well distributed in bone, urine (except moxifloxacin), kidney and prostatic tissue
renally cleared for all except moxifloxacin which is hepatically metabolised
what are the indications for ciprofloxacin
gram neg incl penicillin cephalosporin and aminoglycoside resistant strains, only PO agent for pseudomonas, food poisoning caused by enterobacteriae (salmonella, shigella, e coli) and campylobacter, traveller’s diarrhoea caused by e coli, typhoid fever caused by salmonella and anthrax
what conditions of ciprofloxacin not used for
simple uti and MRSA
why is ciprofloxacin not used for MRSA
ineffective against anaerobes and is highly resistant to staphylococcus
what is levofloxacin and mixofloxacin known as
respiratory quinolones
what are the indications of respiratory quinolones
better coverage against gram pos, atypicals and mycobacterium
what are the indications of respiratory quinolones
better coverage against gram pos, atypicals and mycobacterium
what are the adverse effects of fluoroquinolones
- GI
- risk of dysglycemia
- aortic dissections or rupture of aortic aneurysm
- increase risk of c. difficile due to clearing of bowel flora esp with ciprofloxacin
- phototoxicity
- light headedness, dizziness and headache
- joint problems (not for <18yo)
- increase risk of tendonitis or tendon rupture due to systemic use
- peripheral neuropathy (affect tendon, muscle, joints, nerves and can occur any time and last for months or even permanent even after stopping)
- QT prolongation (third gen esp)
can fluoroquinolones be used in pregnancy
category C due to atropathy (fetal cartilage development disorders) and ciprofloxacin detected in breast milk
what are the c/i of fluoroquinolone
myasthenia gravis, muscle weakness, g6pd deficiency
what are the fdi of fluoroquinolone
ingestion with Ca or other divalent or trivalent cations can reduce absorption (Al, Fe, Mg, Zn)
what are the ddi of fluoroquinolone
raise serum level of warfarin and cyclosporin
what is folic acid
vitamin B that helps make RBC
what is the folic acid synthesis pathway
pteridine and PABA -> dihydropteroic acid [dihydropteroate synthease] -> dihydrofolic acid [dihydrofolate synthase] -> tetrahydrofolic acid [dihydrofolate reductase with NADH] -> AA, purine, thymine synthesis
what are the drugs that are anti folate drugs
sulfonamides and trimethoprim
what is the moa of sulfonamides
competitive inhibitor of dihydropteroate synthase enzyme upstream which is the bacterial enzyme that incorporates para-aminobenzoic acid (PABA) into dihydropteroic acid which is the immediate precursor of folic acid
what type of activity does sulfonamides have
bacteriostatic
are mammalian cells affected by the mechanism of sulfonamides
no, we require preformed folic acid (only have step from conversion of dihydrofolic acid into tetrahydrofolic acid)
what is the moa of trimeptoprime
potent inhibitor of dihydrofolate reductase enzyme which inhibits the reduction of dihydrofolic acid into tetrahydrofolic acid which leads to a decreased availability of tetrahydrofolate cofactors required for AA, purine and thymine synthesis which will affect DNA synthesis as a whole
what is the benefit of coadministering sulfonamides and trimeptoprime
introduces sequential blocks in biosynthetic pathway for tetrahydrofolate which allows for synergistic effect
what are the types of sulfonamides and examples of drugs of each type
short acting - sulfisoxazole
intermediate acting - sulfadiazine, sulfamethoxazole
poorly absorbed (active in bowel lumen) - sulfasalazine
topically applied - silver sulfadiazine, sulfacetamide
long acting - sulfadoxine
what are the absorption, distribution, metabolism and excretion characteristics of sulfonamides
absorption: well absorbed after oral administration
distribution: bound to serum albumin and can displace other things bound to serum albumin, distribute throughout bodily fluids and can penetrate into csf even without inflamm, pass placenta barrier and enter fetal tissues
metabolism: acetylation and conjugation occur in liver, byproducts are devoid of antimicrobial activity but has the potential to cause toxicity as it can precipitate in neutral or acidic pH and cause crystaluria which can damage the kidney
excreted by glomerular filtration and secretion, renal dose adjustments needed, may be secreted into breast milk
what are the indications for sulfonamides
pneumocystis (cotrimoxazole), drug resistant malaria and toxoplasmosis (with pyrimethamine), ibs (sulfasalazine), infected burns (topical silver sulfadiazine), STI, respiratory tract infections, acute UTI
what are the indications for sulfonamides
pneumocystis (cotrimoxazole), drug resistant malaria and toxoplasmosis (with pyrimethamine), ibs (sulfasalazine), infected burns (topical silver sulfadiazine), STI, respiratory tract infections, acute UTI
what are the adverse effects of sulfonamides
- crystalluria
- hypersensitivity
- hematopoietic disturbances (hemolytic anemia and thrombocytopenia)
- kernicterus
what is the ddi for sulfonamides
warfarin with sulfamethoxazole
what is the c/i for sulfonamides
newborns, infants <2m, pregnant at term
in which special population might hemolytic anemia occur and what drug is it
sulfonamides can cause hemolytic anemia in g6pd deficient as sulfa drugs produces alot of ROS/ free radicals which will not be removed if deficient
which drug can cause kernicterus and why
sulfonamides can cause kernicterus in newborns as sulfa drugs can displace bilirubin from serum albumin which results in free bilirubin that can cross into cns as bbb is not fully developed and not very effective liver function thus leading to neurodamage and affect brain development
what are the indications for trimethoprim
enterobacter species (ecoli, klebsiella), monoagent for UTI and bacteria prostatitis but fluoroquinolones preferred
what are the mechanisms of resistance for trimethoprim
- altered dihydrofolate reductase which has lower affinity for trimeptoprim
- presence of efflux pumps and decreased permeability to drug
absorption, distribution and excretion of trimethoprim
absorption: rapidly absorbed after oral adminstration, weak base so higher conc achieved in relatively acidic prostatic and vaginal fluids
distribution: widely distributed to bodily tissues and fluids, good penetration into csf
excretion: 60-80% unchanged renally, renal dose adjustments required
what are the adverse effects of trimethoprim
- folic acid deficiency (megaloblastic anemia, leukopenia, granulocytopenia in pregnant and those with very poor diets)
what might trimethoprim cause in pregnant patients
folic acid deficiency
which drug causes folic acid deficiency and how to manage
trimethoprim and manage by simultaneously administering folinic acid
what is folinic acid and how does it help reverse folic acid deficiency
is a 5-formyl derivative of tetrahydrofolic acid which readily converts to tetrahydrofolic acid which is required for important cellular metabolic functions, does not enter bacteria and is not dihydrofolic acid which requires to be reduced into active form
what is cotrimoxazole
1:5 ratio of trimethoprime and sulfamethoxazole
what is the moa of cotrimoxazole
synergistic antimicrobial activity derived from inhibiting two sequential steps in synthesis of tetrahydrofolic acid
what are the indications for cotrimoxazole
UTI, e coli, prophylaxis for recurrent UTI, RTI (klebsiella, moraxella catarrhalis, haemophilus), MRSA, community acquired skin and soft tissue infections, pneumocystis pneumonia
absorption, distribution and excretion of cotrimoxazole
absorption: PO with full cup of water, IV for severe pneumonia or UTI if unable take by mouth
distribution: both distribute well throughout body, trimethoprim conc in relative acidic fluids, good csf penetration
excretion: parent and metabolites excreted in urine
what are the ddi of cotrimoxazole
increases half life of phenytoin, enhances effect of warfarin
what are the adverse effects of cotrimoxazole
- skin rash
- photosensitivity
- GI (N, V)
- glossitis, stomatitis (hemolytic anemia in g6pd deficient due to sulfamethoxazole, megaloblastic anemia/ leukopenia/ thrombocytopenia due to trimethoprim)
- folic acid deficiency (caution in pregnancy)
what special population to take note of for cotrimoxazole
g6pd deficient and pregnancy
which trimesters should cotrimoxazole especially not be used in
first trimester as pregnancy very sensitive to folate levels, third trimester not sure if child is g6pd deficient
what class of drug is nitrofurantoin
urinary antiseptic
what is the moa of nitrofurantoin
nitrofurantoin sensitive bacteria reduces the drug to a highly active intermediate that inhibits various enzymes and disrupts the synthesis of DNA, RNA and proteins, and metabolic processes
what are the indications for nitrofurantoin
acute lower UTI, prophylaxis for recurrent UTI
what is the spectrum of activity of nitrofurantoin
e coli, enterococci
what bacteria is resistant to nitrofurantoin
klebsiella, pseudomonas, proteus, enterobacter
what pH does nitrofurantoin work best in
activity higher in acidic urine pH <5.5
does nitrofurantoin colour urine
yes colours it brown
absorption, distribution and excretion of nitrofurantoin
absorption: PO absorbed rapidly from GIT
distribution: achieves high urinary conc while limiting systemic exposure due to rapid clearance
excretion: 40% excreted unchanged in urine, rate of excretion linearly related to CrCl so decrease efficacy and increase toxicity if impaired glomerular function
is macrocrystalline form of nitrofurantoin absorbed more rapidly or more slowly
absorbed and excreted more slowly than nitrofurantoin
what are the adverse effects of nitrofurantoin
- GI (N,V,D) -> macrocrystalline preparation better tolerated
- hypersensitivity
- cholestatic jaundice and hepatocellular damage
- pulmonary toxicity esp in older adults
- peripheral neuropathy in impaired renal function and long treatment
- prolonged incubation period to onset of liver injury
how does nitrofurantoin cause cholestatic jaundice and hepatocellular damage
nitro reductive metabolism produces injurious oxidative free radicals which damages hepatocytes
what are the c/i of nitrofurantoin
- renal impairment (CrCl <40ml/min)
- pregnant (38-42w gestation), during labour and delivery as unsure if child is g6pd deficient
what are the types of UTI
nephritis and pyelonephritis
what is nephritis
bladder infection
what is pyelonephritis
kidney infection
what are the symptoms of nephritis
increased urinary frequency, urgency, dysuria (painful urination), pain above pubic region, WBC and bacteria in urine, possible hematuria, more common in women
what are the symptoms of pyelonephritis
flank pain, high fever, malaise, WBC ans bacteria in urine, urinary symptoms similar to nephritis
what is the first line drug for nephritis and pyelonephritis
nephritis: nitrofurantoin
pyelonephritis: IV ceftriaxone
what is the first lie drug for ESBL
carbapenems
what is a anti-protazoal agent
metronidazole
where are protozoal infections common in
underdeveloped tropical and subtropical countries
what is the characteristics of protozoal cells
protozoal cells are unicellular eukaryotic cells with a clearly defined nucleus and has metabolic processes that are similar to those of human host than to prokaryotic bacterial pathogens
what is amebiasis
an infection of the intestinal tract caused by entamoeba histolytica
what are the types of agents used for amebiasis
luminal, systemic and mixed amebicides chemotherapeutic agents
what does luminal chemotherapeutic agents act on
act on parasite in bowel lumen
what does systemic chemotherapeutic agents act on
act on amoebas in intestinal wall and liver after being absorbed
what are mixed amebicides used for
effective against both luminal and systemic although luminal conc not high enough for single drug treatment
what is an example of a mixed amebicide agent
metronidazole
is metronidazole safe in pregnancy
category B, avoid use in first trimester, not proven safe and crosses placental barrier and enters fetal circulation rapidly
what is the moa of metronidazole
amoebas possess an electron transport protein that participate in metabolic electron removal reactions and since metronidazole has a nitro group it can serve as an electron acceptor to form cytotoxic free radicals which causes protein and DNA damage and leads to cell death
what are the conditions for reduction of metronidazole to exert its moa
anaerobic conditions as anaerobes have better reducing potential than aerobes
what are the indications for metronidazole
- amebic infections caused by protozoa
- anaerobes like bacteriodes, c. difficile
- h pylori
- surgical prophylaxis
absorption, distribution, metabolism and excretion of metronidazole
absorption: completely and rapidly absorbed after oral administration
distribution: well distributed throughout bodily tissues and fluids (vaginal, seminal fluid, saliva, breast milk), good csf penetration
metabolism: hepatic metabolism (drug accumulates in severe hepatic disease, concomitant administration of cyp inhibitors or inducers can affect rate of drug metabolism)
excretion: parent and metabolites excreted in urine
what are the adverse effects of metronidazole
- GI
- unpleasant metallic taste
- oral moniliasis (yeast infection of mouth)
- central and peripheral nervous system effects (convulsive seizures, optic and peripheral neuropathy)
