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SULFONAMIDES - Coggle Diagram
SULFONAMIDES
Chemistry
- Structural similarity to PABA
- Differ in R-group attached to amido/amino grp. of sulfanilammide nucleus
- More soluble at alkaline pH
- Free amino group at p-position(N4) confer antibacterial property
- 1st Antimicrobial agents eff. against pyogenic inf.
- Protonsil Red ( Sulfonamido-chrysoidine): Domagk→ expt. strep. inf. in mice
- Resistance→ now used as combination only
ANTIMICROBIAL SPECTRUM
:check:
- Bacteriostatic against G+ & G-ve
- Bacteriocidal conc. attained in urine
- Strep. pyogenes, H. influenzae, H. ducreyi, Calymmatobacterium granulomatis, V. cholerae
- Only a few Staph. aureus, gonococci, meningococci, pneumococci, E.coli, Shigella respond
- Enterobacter sp. , Nocardia, Chlamydia trachomatis, Actinomyces, some protozoa
- Rickettsial growth is stimulated(not inhibited)
- Poor activity against anaerobes
MOA :check:
- Sulfonamide susceptible org. synthesize their own Folic Acid from PABA
- Sulfonamides compete with PABA → inhibit Dihydropteroate synthase→ inhibit FA pdn.
- May get incorporated to form altered FA→ metabolically injurious
-
RESISTANCE
:check:
- Occur as a result of mutations that
○ Cause overpdn. of PABA
○ cause pdn. of a FA synthesising enzyme that has low affinity for sulfonamides
○ impair permeability to sulfonamides
○ adopt alt. pathway for FA synthesis
- Dihydropteroate sythase with low sulfonamide affinity→ encoded on a plasmid→ disseminate rapidly & widely
PHARMACOKINETICS :check:
- Rapidly & nearly completely absorbed from GIT
- 3 major groups
○ Oral absorbable
○ Oral non-absorbable
○ Topical
- Extent of PPB differs (10-95%)
- High PPB→ longer acting
- Widely distributed → enter serous cavities easily & even CSF & placenta
- Metabolism
○ Acetylation at N4 by nonmicrosomal acetyl transferase→ in liver
○ Acetylated deivative is inactive → adverse effects
○ Less soluble in acidic urine than parent drug→ ppt→ crystalluria
- Theraputic conc: 40-100mcg/mL of blood
ADVERSE EFFECTS :check:
- Relatively common
- Nausea, vomiting, epigastric pain
- Dose related crystalluria
○ Reduced by taking plenty of fluids & alkalinizing urine
- HS reactions in 2-5% patients
○ Rashes, urticaria
○ Drug fever
○ Stevens-Johnsons syndrome & Exfoliative dermatitis in long acting agents
- Hepatitis unrelated to dose in 0.1%
- Hemolysis @ high dose→in G6PD def. patients
- Rare→ neutropenia, other blood dyscrasias
- Kernicterus in newborn(premature)
USES
- Not used as single agents
- FDC of trimethoprim-sulfamethoxazole is DOC for infections like Pneumocysis jiroveci pneumonia, toxoplasmosis, & nocardiosis
A. Oral Absorbable Agents
- A/c toxoplasmosis
○ Sulfadiazine+ pyrimethamine→ 1st line
○ Synergistic action of combination
- Sulfadoxine(long acting) + pyrimethamine→ Fansidar
○ 2nd line for malaria
B. Oral Non-absorbable Agents
- UC/ enteritis/ IBD
○ Sulfasalazine
C. Topical Agents
- Sod. sulfacetamide ophthalmic soln. or ointment
○ Bacterial conjunctivitis
○ Adjunctive therapy of trachoma
- Mafenide acetate
○ Topically used, for burns wound
○ Drug & primary metabolite→ inhibit CA→ metabolic acidosis
○ This S/E limits use
- Silver sulfadiazine
○ Preventing infection of burn wounds
○ Preferred to mafenide
DRUGS
SULFAMETHOXAZOLE
- Slow oral abs. & urinary excr.
- Intermediate duration of action
- Preferred for combi. with trimethoprim( similar T½)
- High conc. of acetylated fraction→ crystalluria
SULFADOXINE, SULFAMETHOPYRAZINE
- Ultralong acting
- Action >1wk d/t high PPB & slow excr.
- Used in combi. with pyrimethamine
○ Malaria
○ Pneumocystis jiroveci pneumonia in AIDS patients
○ toxoplasmosis
- Low plasma conc.→ not suitable for a/c pyogenic inf.
- Serious cutaneous reactions
SULFACETAMIDE SOD.
- Highly soluble compound yielding neutral soln
- Only mild irritation to eye in ~30% conc.
- Used topically for ocular infections
○ bacteria & chlamydia
○ ophthalmia nenatorum by Ch.oculogenitalis
- Low sensitivity reactions
COTRIMOXAZOLE
FDC of Trimethoprim + Sulfamethoxazole Trimethoprim
- Diaminopyrimidine related to antimalarial drug Pyrimethamine→ selectively inhibits DHFRase
Features
- Sequential block of FA metabolism
- Component drugs are individually bacteriostatic, but combination is bacteiocidal
- Max synergism→ when organism is susceptible to both components
- Sulfamethoxazole & trimethoprim~ nearly same T½
- Optimal synergy at conc. ratio
Sulfamethoxazole 20: trimethoprim 1
- MIC of each component is ↓ by 3-6times
- This plasma ratio is attained when drug is administered in a dose ratio 5:1
○ Trimethoprim more lipid soluble→ enters many tissues→ larger Vd
○ More rapidly absorbed- trimethoprim
- Trimethoprim: 40% PPB
- Sulfamethoxazole: 65% PPB
- Partly metabolised in liver & excreted in urine
SPECTRUM :check:
- Spectra of trimethoprim+ sulfonamides
- Additionally:
Salmonella typhi, Serratia, Klebsiella, Enterobacter, Yersinia enterocolitica, Pneumocystic jiroveci
- Many other sulfonamide resistant strains of
Staph. aureus, Strep. pyogenes, Shigella, EPEC, H. influenzae, gonococci, meningococci
RESISTANCE
- Resistance to trimethoprim
○ Plasmid mediated acquisition of DHFRase having low affinity for inhibitor
- Resistance to combi. is slow to develop
ADVERSE EFFECTS
:warning:
- Nausea, vomiting, headache
- Stomatitis, rashes
- Folate deficiency→ megaloblastic anemia in patients with marginal folate levels
- Rarely blood dyscrasias
- C/I in Pregnancy
○ trimethoprim→ antifolate→ theoretical teratogenic risk
○ Neonatal hemolysis/ methemoglobinemia can occur near term
- Patients with renal disease
○ develop uremia
○ dose to be reduced
- Among AIDS patients with Pneumocystis jiroveci infection
○ 50% incidence of fever , rash, bone marrow hypoplasia
- Elder patients
○ risk of bone marrow toxicity
- Diuretics+ cotrimoxazole→ higher incidence of thrombocytopenia
USES :check:
- UTI
○ Most a/c uncomplicated inf.→ rapid response
○ A/c cystitis→ Single dose therapy with 4 tab. cotrimoxazole
○ C/c or recurrent cases, prostatitis → trimethoprim is conc. in prostate d/t relatively acidic nature of prostatic fluid
- Resp. tract inf.
○ URTI/LRTI, c/c bronchitis, facio-maxillary infections, otitis media
○ by G+ cocci, H influenzae, Moraxella catarrhalis
- Bacterial diarrheas & dysentery
○ Severe and invasive infections by E.coli, Shigella, non-typhoid Salmonella, Y. enterocolitica
○ Now fluoroquinolones are commonly used
- Pneumocystis jiroveci
○ Prophylactic & therapeutic value
○ High doses required
○ One DS tab 4-6times/d for 2-3 weeks
MAFENIDE
- Not typical sulfonamide
- Used topically→ inhibits a variety of G+ & G- bacteria
- In contrast to other sulfonamides→
○ Active in presence of pus
○ Against Pseudomonas, clostridia
- For Burns dressing to prevent infections
- Limitation: burning sensation & severe pain when applied to raw surface
- Rapidly absorbed from raw surface
- Mafenide & metabolite are CA inhibitors→ Acidosis & hyperventilation
- Allergic reactions, rashes common
SILVER SULFADIAZINE
- Active against bacteria, fungi, pseudomonas
- Slowly releases silver ions→ antimicrobial action
- Use: prevent infection of burnt areas & c/c ulcers
- Well tolerated
- Local S/E: burning sensation on application & itch
- Released sulfadiazine may be absorbed systemically & cause ADR
SULFASALAZINE : Use: UC, RA