Transcript 4-Metabolic & NA Inhibitor(Lec.1&2)

Reading assignments:
Katzung’s Basic & Clinical Pharmacology,
13th Edi ,Ch-46,p807-814;
LEARNING OBJECTIVES
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D. Inhibitors of folate-dependent pathways
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Understand the production and use of folate derivatives in bacterial
systems
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1. Sulfonamides
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2. Trimethoprim
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Understand the function of DNA gyrases, and the effects of their inhibition
Know the clinical uses of quinolones and fluoroquinolones
Know the adverse effects and potential drug-drug interaction for quinolones
F. Nitroimidazoles
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Know the mechanism of action of trimethoprim
Understand the rationale of combined sulfonamide-trimethoprim chemotherapy
Know the clinical uses and adverse effects associated with trimethoprim
E. DNA gyrase inhibitors
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Know the mechanism of action of sulfonamides
Understand the concept of "antimetabolite"
Appreciate the role of pharmacokinetics in the action and uses of sulfonamides
Know the pharmacokinetic and pharmacodynamic differences among various
sulfonamides
Know the adverse effects of sulfonamides
Understand the mechanism of action of Metronidazole & tinidazole
Know the clinical uses
Know the adverse effects and potential drug-drug interaction
G. Urinary tract antiseptics
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Understand the role of pharmacokinetics in the treatment of urinary tract infections
D. Inhibitors of folate-dependent pathways
1. Sulfonamides
SULFISOXAZOLE
SULFAMETHOXAZOLE (1)
SULFASALAZINE (SALICYLAZOSULFAPYRIDINE)(2)
SODIUM SULFACETAMIDE
SILVER SULFADIAZINE (3)
CO-TRIMOXAZOLE
(SULFAMETHOXAZOLE/TRIMETHOPRIM) (7)
2. Dihydrofolate reductase inhibitors
TRIMETHOPRIM (bacteria) (4)
PYRIMETHAMINE (protozoa) (5)
METHOTREXATE (mammalian) (6)
Anti-Metabolites: Anti-Folates
Two Classes—
Inhibitors of folate synthesis
– p-Aminobenzoic acid analogs
(PABA)
Inhibitors of folate use
– dihydrofolate reductase inhibitors
• Trimethoprim – bacterial
• Pyrimethamine – protozoa
• Methotrexate - mammalian
Mechanism
• PABA analogs
Sulfonamides
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Enter into a normal metabolic pathway, but then block that pathway
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Competitive inhibitor of dihydropteroate synthase
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Bacteriostatic
Pharmacokinetics
• Oral, some topical (burns), rarely IV
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Well absorbed from GI, high PPB, well distributed including to CNS
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Variable metabolism, depending on drug and patient
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Acetylation yields inactive metabolite (less water soluble)→ Crystalluria
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Excreted in urine (90% by glomerular filtration)
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10-20x blood concentration in urine
Sulfonamides: Clinical Aspects
Clinical Use-• Topical for burns--Silver sulfadiazine
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Ophthalmic preparations – Sodium sulfacetamide
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Urinary Tract Infections-- Uncomplicated, untreated, acute
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Ulcerative colitis-- Sulfasalazine, Mesalamine
– Not absorbed-- split by gut bacteria reductase to release 5-aminosalicylate
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Sulfonamides now are seldom used as single agents-- combine with
trimethoprim
Sulfonamide alone is almost never used as an antibiotic
Adverse Effects-• Allergic reactions-- fever, rash, etc.
– Up to 5% incidence
– Cross-reactivity with other sulfonamides-- carbonic anhydrase
inhibitors, thiazides, furosemide, sulfonylurea hypoglycemics
– Crystalluria
Sulfonamides: Clinical Aspects
Adverse Effects–
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Stevens-Johnson syndrome—(Type IV)
– Fever, malaise, . . .
– Rare, but can be fatal
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Hematopoietic effects
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Hemolytic anemias-- G6PDH deficiency
Drug Interactions
Kernicterus in newborns
Resistance-• Mutations causing overproduction of PABA
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Loss of permeability
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New form of dihydropteroate synthetase-discriminates between PABA and
sulfonamide
Dihydrofolate Reductase Inhibitors
• Trimethoprim-- blocks bacterial enzyme
• Pyrimethamine-- protozoan enzyme
• Methotrexate-- mammalian enzyme
Trimethoprim-• Readily absorbed from GI
• Wide distribution, including CNS
• Excreted in urine
• Can be used alone for UTI, but usually combined with a
sulfonamide
Trimethoprim-Sulfamethoxazole (Cotrimoxazole)
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Combination is often bactericidal
DOC in Nocardia
Mycobacteria
Gm-ve Infections
(E.Coli, Salmonella,Shihella)
• Gm+ve Infections
Note: Pneumocystis jiroveci used
( Staph, Strepto, H. Influenzae )to be called Pneumocystis carinii (PCP)
Fungus: Pneumocystis jiroveci pneumonia (PCP)-both
for prophylaxis (when CD4 count <200) & treatment in HIV
infection.
• Protozoa : Toxoplasma Gondii (Sulfadiazine +
Pyrimethamine) both for prophylaxis (when CD4 count
<200) & treatment in HIV infection & in T of STORCH
infection.
Adverse Effects of Trimethoprim
Trimethoprim is 10,000x more effective against bacterial
DHFR than against the mammalian enzyme, but still may
see "anti-folate" effects
• Megaloblastic anemia, leukopenia, granulocytopenia
• Treat with folinic acid
Co-trimoxazole-- Add typical sulfonamide effects
• AIDS patients with Pneumocystis pneumonia (PCP)
receiving Co-trimoxazole-– Much higher incidence of adverse effects
– Fever, rashes, leukopenia, diarrhea
E. DNA gyrase inhibitors
NALIDIXIC ACID
NORFLOXACIN
CIPROFLOXACIN
LEVOFLOXACIN
GATIFLOXACIN
SPAROFLOXACIN
MOXIFLOXACIN
TROVAFLOXACIN
Common ending with ‘floxacin’
Flo-fluorine
DNA
Gyrase
Inhibitors
Quinolones
Nalidixic Acid-•
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Prototype quinolone antibiotic
Inhibits DNA replication
[by inhibiting DNA gyrase (Topoisomerase II)& IV]
Pharmacokinetics
– Oral administration
– Rapidly absorbed, metabolized (Glucuronidated)
and excreted in urine
Fluoroquinolones-–
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Norfloxacin
Ciprofloxacin
Ofloxacin
Levofloxacin
Gatifloxacin
Moxifloxacin
Gemifoxacin
Note: -floxacin ending
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Fluorinated analogues of nalidixic acid
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Pharmacokinetics
– Well absorbed and distributed after oral administration (Iron,Calcium limit
absorption )
– Only 20% is metabolized (liver)
– Excreted in urine, blocked by probenecid
– Effective systemically after oral dose, parenteral forms also available
Fluoroquinolones
• Example 1st Generation: norfloxacin; activity against
common pathogens that cause urinary tract infections;
similar to nalidixic acid
• Examples of 2nd Generation: ciprofloxacin,
ofloxacin; excellent activity against gram-negative
bacteria, including gonococcus, Chlamydia, many grampositive cocci, mycobacteria, and Mycoplasma
pneumoniae
• Examples of 3rd Generation: levofloxacin,
gatifloxacin; less activity against gram-negative bacteria
but greater activity against some gram-positive cocci,
such as S. pneumoniae, entercocci, and MRSA; good for
many drug-resistant respiratory tract infections
• Examples of 4th Generation: moxifloxacin,
Gemifloxacin; broadest spectrum fluoroquinolones with
good activity against anaerobes
Activity & Clinical Uses
-UTIs particularly when resistant to Cotrimoxazole
-STDs/PIDs:Chlamydia (Ofloxacin), Gonorrhea
(Cipro,Ofloxacin)
-Skin, soft tissue & bone infection by gm-ve organisms
(all except norfloxacin)
-Diarrhea due to Shigella ,Salmonella, E.coli,
Campylobacter (any quinolone)
-PNSP (Levofloxacin)
Fluoroquinolones
Adverse Effects-• Nausea and vomiting
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Phototoxicity & rashes (other drugs?)
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All quinolone ↑ QT interval
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Headaches, dizziness, insomnia
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Abnormal liver function tests
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Blocks theophylline clearance-- cannot be co-administered
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Connective tissue disorders including tendonitis or tendon rapture (in adults),
myalgia & leg cramps (in children)
– Do not use during pregnancy or in children (Fluorine is the culprit )
Resistance-• Altered (mutated) DNA gyrase
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Especially Pseudomonas, Staph, Serratia
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No longer recommended for gonococcus because of resistance
• Discuss about the rationality of long term
use of fluoroquinolones in children , adults
or in pregnancy.
F. Urinary tract antiseptics
NITROFURANTOIN
SYSTEMIC AGENTS
Urinary Tract Antiseptics
• Use systemic agents, which are efficiently cleared in the
urine:
– Penicillins
– Aminoglycosides
– Sulfonamides
• Resistance and re-infection are common
• May need to suppress bacteria for a long time
• Common UTI bugs are
E.Coli(m/c), staphylococcus saprophyticus ,enterobacter
cloacae, proteus mirabilis,klebsiella pneumonae,
pseudomonus aeruginosa and serriatia .
Nitrofurantoin
Mechanism
• Unknown, but may involve oxidative stress
• Bacteriostatic or bactericidal (depends on microbe)
Pharmacokinetics-• Rapidly absorbed (oral), metabolized , and excreted in urine (50% as active
drug)
• Even IV nitrofurantoin does not have a systemic effect
Clinical Use-• UTI, gram positive or gram negative microbes
• Most effective if urine pH < 5.5
Adverse Effects-• Anorexia, GI disturbances common, headaches
• Occasional hemolytic anemia (oxidative) especially if G6PDH deficient,
leukopenia, hepatotoxicity
• In renal insufficiency, see systemic toxicity
Resistance-• All Pseudomonas, some Proteus are resistant
Spectrum coverage of Antibiotics covered in a chart.
Antibiotic Sensitivity Overview
Antibiotics of Choice for Various Infections
Drug
Organism (Disease)
Amoxicillin, clarithromycin (omeprazole*) Helicobacter pylori (peptic ulcer)
Ampicillin
Listeria (meningitis)
Ceftriaxone, Cefexime
Neisseria gonorrhoeae (gonorrhea)
Cephalosporins (third-generation)
Haemophilus influenzae
(pneumonia, meningitis)
Klebsiella (meningitis)
Doxycycline
Borrelia burgdorferi (Lyme disease)
Rickettsiae (Rocky Mountain spotted
fever)
Erythromycin
Legionella (legionnaires’ disease)
Fluconazole, miconazole, nystatin
Candida (candidiasis)
Isoniazid, rifampin, ethambutol,
pyrazinamide
Mycobacterium tuberculosis
(tuberculosis)
*Omeprazole is not an antibiotic but is used in combination with antibiotics for treatment of H. pylori.
Antibiotics of Choice for Various Infections
Drug
Organism (Disease)
Macrolides
Mycoplasma pneumoniae (atypical
pneumonia)
Legionella (legionnaires’ disease)
Corynebacterium diphtheriae; Chlamydia
Metronidazole
Trichomonas (trichomoniasis)
Penicillin G
Neisseria meningitidis (meningitis)
Treponema pallidum (syphilis)
Infections caused by streptococci,
pneumococci, other meningococci,
Bacillus anthracis,
Clostridium,
Bacteroides (except B. fragilis)
Fluroquinolones
Campylobacter (diarrhea); Shigella
Tetracycline
Vibrio cholerae (cholera)
Other tetracyclines
Chlamydia (pneumonia, lymphogranuloma
venereum)
Trimethoprim-sulfamethoxazole
Salmonella; Shigella (diarrhea)
Metronidazole or vancomycin (oral)
Clostridium difficile (diarrhea)
Prophylactic Use of Anti-infective Drugs
Drug
Cefazolin
Use
Surgical procedures
Cefoxitin, Cefotetan
Surgical procedures where
anaerobic infections are
common
Ampicillin or penicillin
Group B streptococcal infections
Trimethoprim-sulfamethoxazole
Pneumocystis carinii pneumonia (PCP)
UTIs
Rifampin
Haemophilus influenzae type B
Meningococcal infection
Chloroquine
Malaria
Isoniazid
Tuberculosis
Azithromycin
Mycobacterium avium complex (MAC) in patients
with AIDS
Ampicillin or azithromycin
or clindamycin
Dental procedures in patients with valve
abnormalities
AIDS = Acquired immunodeficiency syndrome; UTI = urinary tract infection.
Antibacterial agents
Cell wall synthesis
inhibitors
Protein synthesis
inhibitors
Urinary tract
antiseptics
Nitrofurantoin
Inhibitors of folate
dependent pathways
Systemic agents
Sulfonamides
Sulfisoxazole
Sulfamethoxazole
Sulfasalazine
Co-trimoxazole
Dihydrofolate
reductase inhibitors
Trimethoprim
Pyrimethamine
Methotrexate
Antimycobacterial drugs
Isoniazid
Ethambutol
Rifampin
Rifabutin
Pyrazinamide
Streptomycin
DNA gyrase
inhibitors
Nalidixic acid
Ciprofloxacin
Norfloxacin
Ofloxacin
Levofloxacin
-floxain
A 44-year-old woman recently exposed
to influenza experiences a headache, fever,
malaise and a cough. These symptoms
subside after 5 days but on the 8th day her
cough worsen and she again has a fever.
Physical examination reveals signs of
pneumonia. Which of the following
medications would be most appropriate for
the treatment of pneumonia in this patient?
A.
B.
C.
D.
E.
Amantadine
Levofloxacin
Palivizumab
Ribavirin
Sulfamethoxazole
Answer: B
Levofloxacin is a
respiratory fluoroquinolone
PowerPoint Slides
 Several of the PowerPoint slides are Copyright © 2002-04,
the American Society for Pharmacology and Experimental
Therapeutics (ASPET). All rights reserved.
 Some of slides in this session are from the above mentioned format
and are free for use by members of ASPET.
 Some others are from various sources like text book, recommended
books, slides of Dr. S. Akbar (ex. professor, Pharmacology ,MUA).
 Core concepts of various USMLE High yield review series like
Kaplan ,BRS etc. are thoroughly explored & integrated whenever
necessary