sulfonamides, trimethoprim, nitrofurantoin, methanamine lecture 18 Flashcards Preview

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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.



Pharmacokinetic properties sulfonamides: excretion

excreted via glomerular filtration; extent varies with agent


AE: sulfonamides


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)


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.