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Autonomic Nervous System

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Autonomic Nervous System
Chemotherapeutic Agents
• Antibiotics
• Antifungals
• Antivirals
• Antiprotozoal
• Antihelmintics
BIMM118
• Anticancer drugs
Antibiotics
General Aspects:
• Principle:
inhibit growth of bacteria without harming the host
– Drug must penetrate body tissue to reach bacteria (exception: GI infection)
(unique targets: cell wall, protein synthesis, metabolic pathways…)
– Bacteria targeted must be within the spectrum of the AB
– Drug can be bactericidal or bacteriostatic
– Different agents can be combined for synergistic effect
(Note: not all combinations are useful, e.g. cell wall synthesis inhibitors loose effectiveness
when combined with bacteriostatic drugs)
– Identification of the invasive microorganism necessary for optimal treatment
• General side effect:
Alteration in normal body flora
BIMM118
– GI tract harbors symbiotic bacteria which are killed by AB =>
resistant bacteria repopulate the niche = secondary or superinfection
(most common: overgrowth of Clostridium difficile)
Antibiotics
• Resistance:
loss of efficacy of a given AB against a particular strain
– Frequently: Staphylococcus aureus, pseudomonas aeruginosa, mycobacterium
tuberculosii
Acquisition:
– Spontaneous mutation
– Adaption: drug metabolism (b-lactamase); alternative metabolic pathways
– Gene transfer: plasmids (via conjugation and transduction); transposons
Manifestation:
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–
–
–
Microbes may increase manufacture of drug-metabolizing enzymes (penicillins)
Microbes may cease active uptake of certain drugs (tetracyclines)
Changes in receptors which decrease antibiotic binding and action
Microbes may synthesize compounds that antagonize drug actions
– Antibiotic use promotes the emergence of drug-resistant microbes
(especially the use of broad-spectrum antibiotics)
BIMM118
!!! The more ABs are used, the greater the chance of resistance !!!
Antibiotics
• Resistance avoided/delayed by:
– Using AB only when absolutely needed and indicated:
AB often abused for viral infections (diarrhea, flu-symptoms, etc.)
– Starting with narrow-spectrum drugs
– Limiting use of newer drugs
– (Minimizing giving antibiotics to livestock)
– Identifying the infecting organism
– Defining the drug sensitivity of the infecting organism
– Considering all host factors:
site of infection, inability of drug of choice to penetrate the site of infection, etc.
– Using AB combinations only when indicated:
Severe or mixed infections, prevention of resistance (tuberculosis)
BIMM118
Worldwide more than 500 metric tons antibiotics are used anually !!!
Antibiotics
Classification:
•
Cell wall synthesis inhibitors
– Beta-lactams (penicillins, cephalosporins, aztreonam, imipenem)
– Poly-peptides (bacitracin, vancomycin)
•
Protein synthesis inhibitors
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–
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•
Aminoglycosides
Tetracyclins
Macrolides
Chloramphenicol
Clindamycin
Folate antagonists
– Sulfonamides
– Trimethoprim
BIMM118
•
Quinolones
Antibiotics - Cell wall synthesis inhibitors
Bacterial cell wall:
Three types:
• Gram-negative (e.g. E.coli, Salmonella)
– Few peptidoglycan layers
(Lipopolysaccheride)
• Gram-positive (e.g. Staphylococci, Listeria)
– Many peptidoglycan layers
(Lipoteichoic acid)
– Stains w/ crystal-violet/iodine
• Acid-fast positive (Mycobacteria)
– Cell wall contains waxy substance
(Mycolic acid)
BIMM118
– Stain w/ acid fast test (heating required)
Antibiotics - Cell wall synthesis inhibitors
Beta-lactam antibiotics:
Q u ic k T im e ™ a n d a
T I F F ( Un c o m p r e s s e d ) d e c o m p r e s s o r
a r e n e e d e d t o s e e t h is p ic t u r e .
1928 - Alexander Fleming observes the antibacterial effects of Penicillin
1940 - Florey and Chain extract Penicillin
Classification:
•
Penicillins
BIMM118
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Narrow spectrum – penicillinase sensitive
Narrow spectrum – penicillinase resistant
Broad spectrum penicillins
Extended-spectrum penicillins
•
Cephalosporines
•
Carbapenems
•
Monobactams
•
Vancomycin, Bacitracin
Antibiotics - Cell wall synthesis inhibitors
Penicillins
Inhibit transpeptidase required for cross-linking peptidoglycan chains
Also inactivate an inhibitor of an autolytic bacterial enzyme => lysis
Narrow spectrum – penicillinase (= b-lactamase) sensitive
•
Benzylpenicillin
– Naturally occuring
– Poor oral availability (sensitive to stomach acid)
=> given by injection
– Active against gram-positive bacteria
BIMM118
•
Phenoxymethylpenicillin
– Better oral availability (acid resistant)
Antibiotics - Cell wall synthesis inhibitors
Narrow spectrum – penicillinase (= b-lactamase) resistant
•
Methicillin
–
–
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Semisynthetic
Poor oral availability (only parenteral)
Active against gram-pos bacteria
Mostly used for Staphylococcus aureus
Oxacillin
BIMM118
– Good oral availability
•
Cloxacillin
•
Dicloxacillin
Antibiotics - Cell wall synthesis inhibitors
Broad spectrum – penicillinase (= b-lactamase) sensitive
(= Aminopenicillins)
•
Ampicillin
–
–
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•
Semisynthetic
Good oral availability
Active against gram-pos and gram-neg bacteria
Active against enterobacteria
Amoxicillin
BIMM118
– Excellent oral availability
Antibiotics - Cell wall synthesis inhibitors
Extended spectrum – penicillinase (= b-lactamase) sensitive
(= Carboxypenicillins)
•
Carbenicillin
–
–
–
–
BIMM118
•
•
•
Semisynthetic
Poor oral availability
Active against gram-pos and gram-neg bacteria
Active against Pseudomonas aeruginosa, Klebsiella
Ticarcillin
Mezlocillin
Pipercillin
Antibiotics - Cell wall synthesis inhibitors
Cephalosporines
Derived from Cephalosporium sp. (same antibiotic mechanism as penicillins)
Cross-allergies with penicillins are common
Some CSs antagonize Vitamin K => bleeding
Some CSs block alcohol oxidation => disulfiram effect
BIMM118
Classified into generations:
• 1-4
• Increasing activity against gram-negative bacterial and anaerobes
• Increasing resistance to destruction by beta-lactamases
• Increasing ability to reach cerebrospinal fluid
Antibiotics - Cell wall synthesis inhibitors
First generation – b-lactamase sensitive
•
Cefazolin
– Naturally occuring
– Active against gram-positive bacteria
•
Cephalexin
Second generation – b-lactamase sensitive
•
Cefaclor
– Some activity against gram-neg bacteria
BIMM118
•
•
Cefamandole
Cefoxitin
Antibiotics - Cell wall synthesis inhibitors
Third generation – mostly b-lactamase resistant
•
Cefotaxime
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•
Active against gram-negative bacteria
Active against Pseudomonas aeruginosa
Active against enterobacteria, gonococcus
Penetrates the CNS => used for meningitis
Ceftriaxone
Fourth generation – mostly b-lactamase restistant
•
Cefepime
– Broadest antimicrobial spectrum of any drug
– Used for MDR bacteria and mixed
infections
BIMM118
•
Cefpirome
Antibiotics - Cell wall synthesis inhibitors
Beta-lactamase inhibitors
•
Clavulanic acid
– Irreversible inhibitor of b-lactamase
– Good oral absorption
– Combined with amoxicillin or ticarcillin
BIMM118
•
Sulbactam
Antibiotics - Cell wall synthesis inhibitors
Vancomycin
•
•
•
•
Only effective against gram-positive bacteria
Poor oral absorption => used for GI infections
Used to be the “Magic bullet” for methicillin-resistant
staphylococci, but now staph are becoming V-resistant.
Dose-related ototoxocity:
Tinnitus, high-tone deafness; can progress to total deafness
Bacitracin
BIMM118
•
•
Mixture of polypeptides
Serious nephrotoxicity => only topical use
Antibiotics - Protein synthesis inhibitors
Protein synthesis inhibitors:
Inhibit either the 30s or 50s ribosomal subunit
(bacterial ribosomal subunits differ from
mammalian ones => drugs are selective
for bacterial protein synthesis)
Class based on chemical structure
of the compounds
Drugs need to enter bacteria =>
entry inhibition is a point of drug resistance
• Classification:
BIMM118
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–
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Aminoglycosides (bactericidal)
Tetracyclins
Macrolides
Chloramphenicol
Clindamycin
Antibiotics - Protein synthesis inhibitors
Aminoglycosides
– Broad spectrum antibiotics (bactericidal)
– Penetration into cell requires an oxygen-dependent transport => anaerobes are
resistant
(Chloramphenicol blocks this transport => inhibits AG uptake into bacteria;
Penicillins weaken the cell wall => promote AG uptake)
– Poor oral absorption (very polar) => parenteral administration
– Narrow therapeutic range - severe side effects:
Ototoxicity: destruction of outer hair cells in organ of Corti
Nephrotoxicity: killing of proximal tubular cells
Neuromuscular toxicity: blockage of presynaptic ACh release => respiratory suppression
– Elimination almost completely by glomerular filtration
BIMM118
(impaired kidney function => concentration of AG increases => toxicity)
Antibiotics - Protein synthesis inhibitors
BIMM118
Aminoglycosides
•
Gentamicin
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•
•
•
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Tobramycin
Streptomycin
Neomycin
Kanamycin
Amikacin
Antibiotics - Protein synthesis inhibitors
Tetracyclines
Penetration into cell requires an energy-dependent transport not present in mammals
Oral absorption impaired by food (insoluble chelates with Ca, Mg => caution w/ antacids)
Side effects:
Incorporation into teeth and bone => staining of teeth; retardation of bone growth
(not used in children and during pregnancy)
Photosensitivity
Broad spectrum antibiotics (bacteriostatic)
Also useful for treating rickettsial diseases (Rocky mountain spotted fever), Spirochetes
BIMM118
(Lyme disease), Mycoplasma (pneumonia)
Antibiotics - Protein synthesis inhibitors
Tetracyclines
•
Tetracycline
–
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Oxytetracycline
Minocycline
Doxycycline
–
–
BIMM118
From Streptomyces sp.
Used to treat rosacea and prevent rhinophyma
No food interaction
Antibiotics - Protein synthesis inhibitors
Macrolides
Narrow spectrum antibiotics similar to penicillin (bacteriostatic or bactericidal)
=> good alternative for patients w/ penicillin allergy
Few side effects (GI disturbances), similar food interaction as tetracyclines
Also used for treating Mycoplasma (pneumonia) and Legionella (Legionnaire’s disease)
•
Erythromycin
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Azithromycin
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Very long half-life (>24 h)
Convient use (Z-Pak®, Zithromax®) - 6 pill regimen
Clarithromycin
–
BIMM118
From Streptomyces erythreus
Used for H. pylori infection
Antibiotics - Protein synthesis inhibitors
Chloramphenicol
Very broad spectrum (almost all bacteria except Pseudomonas aeruginosa)
Very severe side effects
– Bone marrow depression => fatal aplastic anemia
Reserved for life-threatening, otherwise treatment-resistant infections
Clindamycin
Medium broad spectrum (gram-positive organisms, anaerobes)
Used for treatment of penicillin-resistant cocci
Side effects: Colitis (triggered by toxin from clindamycin-resistant Clostridium difficile =>
BIMM118
combined w/ vancomycin to kill C. difficile)
Antibiotics - Folate Antagonsits
Folate antagonists
BIMM118
Bacteria can not absorb folic acid => synthesis from p-amino-benzoic acid (PABA)
required (Folic acid is a vitamin for humans => synthesis pathway is restricted to
bacteria => selective drug target)
Folate antagonsists block folate synthesis => inhibition of nucleotide synthesis =>
bacteriostatic effect
(pus provides alternative source for nucleotides => drugs are inactive in the presence
of pus or necrotic tissue)
Antibiotics - Folate Antagonists
Sulfonamides
Structural analogues of PABA => compete with PABA for Dihydropteroate-synthase
Used for infected burns, STDs, toxoplasmosis…
Note:
Many local anesthetics are PABA-esters => they antagonize folate antagonists
BIMM118
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Sulfadiazine
Sulfadimidine
Sulfamethoxazole
Antibiotics - Folate Antagonists
Trimethoprim
BIMM118
Resembles pteridine moiety of folates => compete with folates for Dihydrofolatereductase
Use similar to sulfonamides
Combined with Sulfomethoxazole (synergistic effect) = Co-trimoxazole (Bactrim®)
Used for urinary tract infections
Antibiotics - Quinolones
Quinolones
BIMM118
Synthetic inhibitors of DNA-Gyrase (= Topoisomerase II), a bacterial enzyme that
winds and unwinds DNA (required for supercoiling the bacterial genome) =>
inhibition of DNA synthesis and transcription
Very broad spectrum, bactericidal - well tolerated
Al and Mg interfer with absorption (antacids!)
Mostly fluorinated = Fluoroquinolones (except nalidixic acid = first quinolone)
Antibiotics - Quinolones
Quinolones
•
Nalidixic acid
– Oldest quinolone
– Only used for urinary tract infections
– Improvement through structure-activity relationship:
• Adding fluorine at position 6 will significantly increase activity
• Substitution of piperazinyl-ring at position-7 will give the drug antipseudomonal activity
•
Ciprofloxacin
– Most commonly used quinolone (Cipro®)
– Very broad spectrum => used for emergencies
(B. anthracis attacks in 2001)
BIMM118
•
•
•
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Levofloxacin
Ofloxacin
Norfloxacin
Travofloxacin …
BIMM118
Antibiotics - Summary
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