Selective toxicity and antibiotics Flashcards
Chemotherapy
Elimination of invading cells / microorganisms / organisms
Chemotherapeutic targets
Mechanisms are associated with the invading species
Effective chemotherapy agents
Are toxic to the invading species / abnormal cells
Relatively non-toxic to the host / normal cells
‘Selectivity toxicity’
Exploits differences between invading species and host.
Differences depend upon evolutionary distances.
Extent of differences has implications for toxicity.
Invading cells/microorganisms/organisms can include
Neoplastic cells: 1. Bacteria (EG Streptococcus species) 2. Viruses (EG Herpes viruses) 3. Fungi (EG Candida albicans) Parasites (EG Protozoa, helminths)
‘Magic bullets’ and Resistance
Paul Enrlich (1845-1915)
Bacterial resistance and antibiotic missuse/overuse have caused serious problems in therapeutic area.
Resistance reduces effective life of a product.
Too little profit, government restrictions, lack of biological targets etc
Antibiotic mode of action - Bacteriostatic
Total cells just above viable cells. Both increase linearly then level off on log cell number-time graph
Antibiotic mode of action - Bacteriolytic
Total cells just above viable cells. Both increase linearly and then decrease linearly on log cell number-time graph
Antibiotic mode of action - Bacteriocidal
Total cells just above viable cells as both increase linearly. Total cells level off and Viable cells decrease linearly once reached maximum log cell number. On log cell number-time graph
Common bacterial targets include…
Cell membrane Cell wall (penicillins) Protein synthesis (macrolides and tetracycline) RNA polymerase DNA synthesis (fluoroquinolones) Folate metabolism (sulphonamides)
Penicillins
Beta lactam ring
A lactam ring is a cyclic amine
A Beta-lactam is a lactam with a heteroatomic ring structure, consisting of 3 carbon atoms and 1 nitrogen atom.
Types of Penicillins
Benzylpenicillin Broad-spectrum penicillins Beta-lactamase-resistant forms Extended-spectrum penicillins Reversed-spectrum penicillins
Benzylpenicillin
Original form
Not very active against gram-negative bacteria
Early penicillins:
-Acid Labile
-Oral route (Not very well absorbed)
-Parenteral route (Slow IV, preferably IM, high availability)
-Narrow spectrum of activity (Gram-positive but only a few gram-negative)
Broad-spectrum penicillins
EG Amoxicillin
More effective against gram-negative bacteria
Broad-spectrum penicillins: Development
Needed derivatives of penicillin which could treat a wider range of infections.
Offered a broader spectrum of activity than either of the original penicillins.
Amino group facilitates penetration of outer membrane of gram-negativev bacteria
Further developments led to amoxicillin with improved duration of action.
Much better absorption profile
Beta-lactamase-resistant forms
Important against β-lactamase producing bacteria.
Penicillins - β-lactam bodies:
-Target the cell wall
-Inhibit the enzyme (transpeptidases) which are responsible for reaction which establishes cross links in the peptidoglycan cell wall.
-Bacterial swell and rupture
-Only effective against multiplying organisms
Bacterial cells walls
Strength and organisation of cell
Dependent on complex polymer - peptidoglycan straight chains cross linked together.
Formation of these cross-links is blocked by penicillin.
Tetrapeptide on N-acetylmuramic acid
Peptidoglycan monomer
N-acetylmuramic acid (NAM)
N-acetyl glucosamine (NAG)
Tetrapeptide
5 glycine molecules then form a chain from one NAM to the next joining at the Lys. (Transpeptidation reaction)
Extended-spectrum penicillins
Effective against pseudomonads
Reversed-spectrum penicillins
Greater activity against gram-negatives than gram-positives
Penicillin pharmacokinetics
Absorption ->
Vary when given orally
Delayed release preparations available (procaine and benzanthine)
Distribution ->
Widely distributed throughout the body although concentrations in tissues and body fluids carry.
Do not normally enter CSF (Except with Meninges inflammation)
Metabolism ->
Short half lives (30-80 mins)
Excretion ->
Mainly through the kidney with 90% excreted by tubular secretion
Clearance reduced in neonates
Reduced excretion rate by use of probenecid, which inhibits tubular secretion.
Penicillins - Adverse reactions
Hypersensitivity -Seen with all penicillins -Skin rashes, fever, anaphylactic shock (rare) -10-15% will show repeat reaction GIT disturbance -Altered gut flora Haemostatic effects -Blood clotting
Sulphonamides
Selectively target metabolic pathways; folate biosynthesis.
Sulphonamides: Folate biosynthesis
Sulphinamides blocks:
pABA + Dihydropteroate synthetase -> Folate
p-amino benzene sulphonamide is a false substrate so blacks pABA from enzyme active site.
Trimethoprim blocks:
Folate + Dihydrofolate reductase -> Tetrahydrofolate
Why is sulphonamide selective?
Folic acid in human cell taken in from diet (Vitamin B9).
Bacterial cells use enzymes in the cell to produce folic acid.
Sulphonamides have a greater affinity towards bacterial versions of the enzymes.
Sulphonamide pharmacokinetics
Absorption -> 80-100% of drug given orally is absorbed from stomach and intestines Distribution -> Widely distributed including CNS Metabolism -> Occurs in liver by N-acetylation Excretion -> In urine ~30 mins
Sulphonamide adverse reactions
Photosensitivity
Stevens-Johnson syndrome (<1% frequency)
Hemopoietic disturbances
Fluoroquinolones
Broad spectrum
Effective against gram-positive and gram-negative
Discovered suring search for administrative drugs.
Fluoroquinolones mechanism of action
Target DNA replication via Type II topoisomerases
Target DNA replication via Type II topoisomerases
1. DNA-gyrase Regulates amount of supercoiling Facilitates movement of transcription and replication complexes through DNA double helix. Removes knots Helps fold DNA 2. DNA topoisomerase IV Homologue of gyrase Unlinks daughter DNA replicons
Typically quinolones inhibit…
DNA-gyrase in gram-negatives
Topoisomerase in gram-positives
Quinolones pharmacokinetics
Absorption -> Oral administration most effective Distribution -> Very well absorbed in upper GI tract Metabolism -> Potent inhibitors of CYP1A2 - Drug-drug interactions Excretion -> Mainly excreted in tubular secretion
Quinolones adverse reactions
Hypersensitivity
GI tract disturbances
Macrolides
Target bacterial ribosomes and protein synthesis
Eukaryotic ribosomes are 80s
Prokaryotic ribosomes are 70s:
-50s and 30s subunits
-50s comprised of 23s and 5s
-50s is the main site of protein synthesis
Target 70s ribosomes, not 80s
Macrolides block translocation of the newly forming peptide
Macrolides - Translation
Initiation Elongation Transpeptidation Translocation (stage affected by macrolides - Binds site near RNA exit tunnel, causes peptidyl-transferase RNA drop off) Chain termination
Macrolide pharmacokinetics
Absorption ->
Oral admin required protected tablets to avoid inactivation by gastric juice.
Distribution ->
Diffuses readily into most tissues but doesn’t cross BBB, crosses placenta
Metabolism ->
Metabolised by demethylation (CYP3A4) can potentiate the effects of other drugs
Excretion -> Excreted in the bile
Macrolide adverse reactions
Cholestatic hepatitis may occur after prolonged use of erythromycin estolate
GIT disturbances seen at large doses
Transitory auditory impairment
Hypersensitivity reactions
Tetracyclines
Target bacterial ribosomes and protein synthesis
Interrupts elongation phase of synthesis
Several binding sites on 30s RNA subunit
Sterically inhibits transfer RNA binding:
>Unbinds
>Rebinds
>Futile loop
Tetracycline pharmacokinetics
Absorption ->
Greater in fasting state and inhibited by concurrent ingestion of dairy products, metal ions and certain antacids.
Distribution ->
Widely distributed entering most tissues
Metabolism ->
Excreted both via the bile and in kidneys by glomular filtration
Excretion ->
Relatively long half lives (6-18 hours due to enterohepatic recirculation)
