Sulfonamides trimethoprim and Quinolones
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Transcript Sulfonamides trimethoprim and Quinolones
Sulfonamides, trimethoprim
and Quinolones
By
S. Bohlooli, PhD
School of Medicine, Ardabil University of Medical Sciences
Antifolate drugs
Sulfonamides
Trimethoprim
Trimethoprim & Sulfamethoxazole
mixture
Sulfonamides: chemistry
Sulfonamides: mechanism of
action
Inhibition of
dihydropetroate
synthase
Sulfonamides: antimicrobial
activity
Gram positive and negative bacteria
Nocardia, chlamydia trachomatis
Some protoza
Some enteric bacteria
Rickettisiae stimulated!
Sulfonamides: resistance
Overproduction of PABA
Low affinity dihydropetroate synthase
Loss of permeability to sulfonamides
Sulfonamides: pharmacokinetics
Oral absorbable
Short
Medium
Long
Oral, nonabsorbable
topical
Serum protein bind
20 ~ 90%
Excreted into urine
Pharmacokinetic Properties of Some
Sulfonamides and Trimethoprim
Drug
Half-Life
Oral Absorption
Sulfacytine
Short
Prompt (peak levels in 1–4 hours)
Sulfisoxazole
Short (6 hours)
Prompt
Sulfamethizole
Short (9 hours)
Prompt
Sulfadiazine
Intermediate (10–17 hours)
Slow (peak levels in 4–8 hours)
Sulfamethoxazole
Intermediate (10–12 hours)
Slow
Sulfapyridine
Intermediate (17 hours)
Slow
Sulfadoxine
Long (7–9 days)
Intermediate
Intermediate (11 hours)
Prompt
Sulfonamides
Pyrimidines
Trimethoprim
Sulfonamides: clinical uses
Oral absorbable agents
Sulfisoxazole, sulfamethoxazole
Sulfadiazine: toxoplasmosis
Sulfadoxine: long acting, in a combination for treatment of
malaria
Oral nonabsorbable agents
To treat urinary tract infection
Ulcerative colitis, enteritis, other inflammatory bowel disease
Topical agents
Sulfacetamide: ophthalemic
Mafenide & silver sulfadiazine: topically
Sulfonamides: adverse reactions
Cross allergenic sulfonamide drugs:
Urinary tract disturbances
Thiazide, furosemide, diazoxide, sulfonylurea hypoglycemic
agents, and others
Fever, skin rashes, exfoliative dermatitis,photosensivity,
urticaria, nausea, vomiting, diarrhea
Stevens-Johnson syndrom
Crystalluria, hemturia, obstruction
Hematopoietic disturbance
Hemolytic or aplastic anemia
Granulocytopenia, thrombocytopenia, leukmoid reaction
Hemolysis in G-6PDH deficient patients
Kernicterus in newborn of mothers have taken near the end
of pergnancy
Trimethoprim: chemistry
Trimethoprim: resistance
Reduced cell permeability
Overproduction of DHF reductase
Altered affinity of reductase
Trimethoprim: pharmacokinetics
Usually given orally alone or in
combination with sulfamethoxazole
Mainly excreted into urine
More antibacterial activity in prostatic
and vaginal fluids
Clinical use
Oral trimethoprim
Oral trimethoprim-sulfamethoxazole
P jiroveci pneumonia, shigellosis, systemic salmonella
infection, complicated urinary tract infection,
Active against many respiratory pathogens
Intravenous trimethoprim-sulfamethoxazole
Acute urinary infection
Gram negative sepsis, pneumocystis pneumonia
Shigllosis, typhoid fever
Oral pryrimethamine with sulfanamide
With sulfadiazine in Leishmaniasis, toxoplasmosis
With sulfadoxine in malaria
Adverse effects
Megaloblastic anemia
Leukopenia, granulocytopenia
Can be prevented by folinic acid
The AIDS patients have high frequency
of unwanted reactions
DNA gyrase inhibitors
Fluoroquinolones
Nalidixic acid and cinoxacin
Fluoroquinolones: chemistry
Fluoroquinolones: chemistry-2
Fluoroquinolones: antibacterial
activity
Block of bacterial DNA synthesis by
Inhibiting topoisomerase II, IV
Gram positive & negative bacteria
Mycoplasma & clamydia, legionella
Some mycobacteria
Anaerobic bacteria
Fluoroquinolones: resistance
Change in permeability
Loss of affinity
Fluoroquinolones: pharmacokinetics
Well absorbed after oral administration
Good distribution
Divalent cations impair absorption
Pharmacokinetic Properties of Fluoroquinolones
Drug
HalfLife (h)
Oral
Bioavailability
(%)
Peak Serum
Concentration
(mcg/mL)
Oral Dose
(mg)
Primary Route of
Excretion
Ciprofloxacin 3–5
70
2.4
500
Renal
Gatifloxacin
8
98
3.4
400
Renal
Gemifloxacin 8
70
1.6
320
Renal & nonrenal
Levofloxacin 5–7
95
5.7
500
Renal
Lomefloxacin 8
95
2.8
400
Renal
Moxifloxacin 9–10
> 85
3.1
400
Nonrenal
Norfloxacin
3.5–5
80
1.5
400
Renal
Ofloxacin
5–7
95
2.9
400
Renal
Fluoroquinolones: clinical uses
Urinary tract infection
Bacterial diarrhea
Even with multi-drug resistant organisms
Shigella, salmonella, toxigenic E. coli
Infections of soft tissues, bones and joints
Intra-abdominal and respiratory tract infections
Gonococcal infection
Chlamydial urethritis and cervicitis
Legionellosis
Tuberclusis and atypical mycobacterial infections
Fluoroquinolones: adverse effects
Nausea, vomiting & diarrhea
Headache, dizziness, insomnia, skin rash,
abnormal liver test
Acute hepatitis & hepatic failure: trovafloxacin
Photosensivity: lomefloxacin, pefloxacin
QT prolongation: sparfloxacin
Hyperglycemia or hypoglycemia
May damage growing cartilage: arthropathy
Tendinitis
Nalidixic acid & cinoxacin
Excreted too rapidly
Useful for urinary tract infections