Transcript Folic acid

Folic acid inhibiting drugs
• Sulfonamides (sulfa drugs)
– Early synthetic drugs
– Metabolic antagonists, block folic acid biosynthetic
pathway
– Folic acid needed for synthesis of nucleotides
• Selectively toxic: folic acid is a human vitamin
– Failure to synthesize DNA bacteriostatic
– Resistance common
• Mutation in enzyme easy
• Reduced drug uptake also occurs
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trimethoprim
• Different structure, functions in same pathway
– Inhibits different enzyme
– Resistance also occurs from changed cell
permeability and altered enzyme
• Used in combinations with sulfonamides
– Bactrim: sulfamethoxazole and trimethoprim
– Synergistic to the point of being bactericidal
– Decreased resistance by mutation from mutation
rate being the product of the two rates
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Folic acid inhibiting combos
sulfamethoxazole
trimethoprim
http://en.wikipedia.org/wiki/Trimethoprim
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Pharmacokinetics and use
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• Sulfa drug family generally administered orally
– Great variation in disposition, half life
– Mostly combos administered
• Wide variety of pathogens including non-bacterial
• Treatment of opportunistic infections found with
HIV infection
• Treatment of urinary tract infections
• Treatment of some chronic respiratory infections
Side effects of folate inhibitors
• Hypersensitivities including Stevens-Johnson
syndrome
– Severe reaction with extensive skin damage and
systemic effects
• Hematological effects including anemias,
agranulocytosis, thrombocytopenia
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Polymyxins
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Cyclic peptides of amino
acids and amino butyric
acid.
“R” is a long hydrophobic
tail.
Source: Bacillus polymyxa
www.cas.astate.edu/
draganjac/AndreaHausman.html
Polymyxins interact with OM of Gram negatives, causing
leakage of periplasmic enzymes, damage cell
membrane.
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Action of Polymyxins
Polymyxins
• Can be used iv with caution
• Toxicity primarily nephro- and neurotoxicity
– Expected to have low selective toxicity because of
detergent effects on cell membranes.
• Typically administered topically along with
neomycin and bacitracin
– Combination covers cell wall inhibition, protein
synthesis inhibition, and membrane attack
– Effective against Gram positives and negatives
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Fluoroquinolones
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• Based on older drug nalidixic acid
• Became familiar to public during anthrax scares
• Inhibit the action of Topoisomerases including
Type 2 (includes gyrase) and Topo..ase IV
– Bacterial DNA is negatively supercoiled; these
enzymes introduce or remove supercoiling and are
required for relieving coiling stress during DNA
replication.
– Inhibition results in cell death due to release of DNA
w/ double strand breaks.
Structure and function
Fluoroquinolone
nucleus:
Drug traps DNAenzyme complex,
releases broken DNA.
Type 2 enzymes
produce double strand
breaks
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Pharmacokinetics and clinical use
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• Fluoroquinolones can all be given orally
– Most can also be administered iv
• Most have fairly long half-life in the body (e.g.
>4 hours), good penetration into compartments
• Mostly renal excretion
• Active against a wide range of bacteria
– Urinary tract and STDs
– Tough to kill bacteria
– Biowarfare agents (anthrax, plague, tularemia)
Toxicity
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Usual wide variety of side effects
GI disturbance including C. difficile problems
Hypersensitivity with rashes
Some degree of neuro- and hepatotixicity
Damage to cartilage in developing individuals
(i.e. children).
• Elevated theophylline levels!
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Chapter 49: anti-mycobacterial agents
• Mycobacterium
– M. tuberculosis: cause of tuberculosis
• Chronic lung disease
– M. avium complex (MAC)
• Environmental opportunist
– M. leprae: Hansen’s disease aka leprosy
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Challenges to treatment
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• Chronic diseases, require long term treatment
• Socio-economic groups
– Homeless and poor least likely to continue therapy,
breeds resistance
• Combination therapy required because of
developing resistance
• Bacteria grow intracellularly
– Drug must reach target
• Uncontrolled, contagious infections in
immunocompromised
Selected info on drugs
• Mixture of synthetic drugs and antibiotics
• Orally administered as befits long term care
– 6 to 9 months of treatment
• Typical drugs:
– Isoniazid, ethambutol, rifampicin, pyrazinamide
– Include many different modes of action
– Some target the unique cell wall consisting of
mycolic acids covalently attached to PG
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Antifungal drugs
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• Fungi are eukaryotes, thus removing targets of
70S ribosomes and PG.
– Major target: fungal cell membrane
– Other drugs target cell wall, nuclear division, and
nucleic acid synthesis
• Except for superficial infections, serious
disease rarely occurs in healthy individual
– Systemic, serious disease in immunocompromised
• Older drugs powerful, but more toxic
– Amphotericin B, Nystatin, etc.
Azoles, Allylamines, Tolnaftate
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• Azoles:Fluconazole, ketoconazole, miconazole
– Inhibit enzyme in ergosterol pathway, compromising
cell membranes
– Some oral, some topical, some iv
• Dependent on absorption properties
• Terbinafine: allylamine marketed as Lamisil
– Concentrated in hair and nails
• Various azoles, terbinafine, and tolnaftate sold
for treatment of superficial infections, OTC
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