sulfonamides, trimethoprim, nitrofurantoin, methanamine lecture 18 Flashcards
Sulfonamides structure and chemistry
all sulfonamides are similar in structure to para aminobenzoic acid (PABA). PABA is a precursor required by bacteria for folic acid synthesis.
MoA sulfonamides
Bacteria require tetrahydrofolic acid (derivative of folic acid), as a cofactor in the synthesis of thymidine, purines, and ultimately DNA.
bacterial cell walls are impermeable to folic acid. Bacteria must synthesize it from PABA.
because of the sulfonamides structural similarity to PABA, they compete with PABA for the enzyme dihydropteroate synthetase; thus depriving the cell of tetrahydrofolic acid.
sulfonadmides may have an increased affinity for the enzyme than the natural substrate, PABA.
Host cells are not affected due to the fact that they require preformed folic acid; they cannot synthesize folic acid.
bacteriostatic
Pharmacokinetic properties sulfonamides: excretion
excreted via glomerular filtration; extent varies with agent
AE: sulfonamides
anaphylaxis
cutaneous reactions: morbilliform rash, stevens johnson syndrome, erythema multiforme, photosensitivity rash.
nephrotoxicity: crystalluria with less soluble compounds (sulfadiazine, sulfathiazole). Administer with fluids
kerncterus: when given in last months of pregnancy compete for bilirubin binding sites on plasma albumin resulting in increased fetal blood levels of unconjugated bilirubin.
SoA sulfonamides
Resistance varies among bacteria.
Gram+: Staph. Streptococcus spp. Bacillus nathracis
G-: haemophilus spp. Providencia, salmonella, shigella, proteus mirabilis/vulgaris, e. coli, klebsiella pneumonia, citrobacter, enterobacter
other: nocardia asteroides, chlamydia trachomatis, toxoplasma gondii, plasmodium falciparum.
Indications: sulfonamides
acute uncomplicated UTI
pneumocystis carinii (treatment and prophylaxis)
nocardosis
toxoplasmosis, malaria (chloroquine-resistant)
rheumatic fever prophylaxis (pcn allergic)
MoA Trimethoprim
trimethoprim is a nonsulfonamide pyrimidine analogue that inhibits dihydrofolate reductase thus preventing the formation of tetra hydrofolic acid
it is ~50,000 times more active against bacterial dihydrofolate reductased than the human enzyme
bacteriostatic or bactericidial depending on the growth conditions
Pharmacokinetics excretion: pharmacokinetics
excreted 80% unchanged, via glomerular filtration and tubular secretion
AE: trimethoprim
Cutaneous reactions: pruritis, rash
gastrointestinal reactions: n/v/d, elevated serum transaminases, bilirubin
use with caution in patients with possible folate deficiency. Alcoholics, debilitated patients, pregnant women, and patients with malabsorptive syndrome.
SoA: trimethoprim
resistance varies among organisms list below. Chart not all inclusive.
G+: staphlococcus spp., Streptococcus spp., bacillus anthracis
G-: proteus mirabilis/vulgaris, e.coli, klebsiella pneumonia, serratia spp., citrobacter spp., enterbacter spp.
other: pneumocystis carinii (only to be used in conjunction with dapsone in patients not tolerant to sulfa/tmp.
MoA: Trimethoprim/sulfamethoxazole
Combined mechanisms of both agents (synergistic). The combination is usually bactericidal and is thought to reduce the rate of emergence of resistance.
Pharm, AE, SoA: Trimethoprim/sulfamethoxazole
similar to their previous but combined.
Indications: trimetoprim/sulfamethoaxazole
UTI: uncompicated UTI, recurrent UTI (prophylaxis)
Respiratory tract infection: acute exacerbations of chronic bronchitis, pneumonia, acute otits media, acute sinusitis, pneumocystis carinii pneumonia (tx and prophylaxis)
gastrointestinal infections: shigellosis, salmonella, travler’s diarrhea, cholera
STD: uncomplicated gonococcal infections, Chancroid
Other infections: nocardosis, malaria (chloroquine resitant, brucellosis, osteomyelitis (Iv agents), strenotrophamonas maltophila (Drug of choice), bacteremia, meningitis, toxoplasmosis, toxoplasmosis prophylaxis in HIV patients, prophylaxis in neutropenic patients
Drug interactions: trimethoprim/sulfamethoaxazole
warfarin: may pitentiate anticoagulant effects. Monitor INR. preferably choose another agent.
Methotrexate: sulfonamides can displace methotrexate from protein binding sites, resulting in an increase in free methotrexate concentrations.
MoA: nitrofurantoin
unclear. possibly interferes with the early stages of bacterial carbohydrate metabolism by inhibiting acetyl coenzyme A.
possible production of reactive 5- nitro anion, free radicals
nitrofurantoin pharmacokinetics
distribution: serum and tissue concentrations are insignificant; urine concentrations are very high
excretion: rate of excretion is linear, related to CrCL; therefore, patients with impared GFR have a decrease in efficacy and an increase in systemic toxicity (do not use if CrCl < 40 ml/min)
AE: nitrofurantoin
pulmonary reactions: acute reactions (hypersensitivity); fever, cough, dyspnea, eosinophilia, LL
infiltrate subacute reaction (after 1 month of therapy), cough, dyspnea, interstitial infiltrate
Chronic reactions: after 6 months of therapy; cough, dyspnea, intersittial infiltrate
gastrointestinal reactions: N/V/D
SoA: nitrofurantoin
G+: staphylococcus aureus, staphylococcus saprophyticus, enterococcus faecalis, enterococcus faecium
G-: escherichia coli, klebsiella pneumonia, citrobacter, enterobacter aerogenes
Indications: nitrofurantoin
acute uncomplicated UTI and UTI prophylaxis
MoA: Methamine
no antibacterial effect alone. At adequate urine pH (
AE: methanmine
Hypersensitivity reactions: rash/pruritis
hemorrhagic cystitis
gastrointestinal reactions: N/V/D
SoA: Methanmin
Virtually all bacteria and fungi are suscptible to formaldehyde. Certain urease + bacteria (proteus) can alkalinize the urine; therefore stopping conversion to formaldehyde.
Formaldehyde concentrations affected by (methamine)
methenamine concentrations in the urine
rate of hydrolysis of the methenamine to formaldehyde
rate of urine loss from bladder by voiding or drainage. Frequent voding of bladder (indwelling catheters or intermittent cath) will decrease effects by removing formaldehyde and by reducing the time of exposure of bladder bacteria to formaldhyde
Indications: methaanamine
UTI proxphylaxis
not recommended for tx of acute UTIs.
