Selective toxicity and antibiotics Flashcards by Caitlin Wood

Chemotherapy

Elimination of invading cells / microorganisms / organisms

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Chemotherapeutic targets

Mechanisms are associated with the invading species

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Effective chemotherapy agents

Are toxic to the invading species / abnormal cells

Relatively non-toxic to the host / normal cells

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‘Selectivity toxicity’

Exploits differences between invading species and host.
Differences depend upon evolutionary distances.
Extent of differences has implications for toxicity.

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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)

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‘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

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Antibiotic mode of action - Bacteriostatic

Total cells just above viable cells. Both increase linearly then level off on log cell number-time graph

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Antibiotic mode of action - Bacteriolytic

Total cells just above viable cells. Both increase linearly and then decrease linearly on log cell number-time graph

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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

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Common bacterial targets include…

Cell membrane
Cell wall (penicillins)
Protein synthesis (macrolides and tetracycline)
RNA polymerase
DNA synthesis (fluoroquinolones)
Folate metabolism (sulphonamides)

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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.

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Types of Penicillins

Benzylpenicillin
Broad-spectrum penicillins
Beta-lactamase-resistant forms
Extended-spectrum penicillins
Reversed-spectrum penicillins

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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)

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Broad-spectrum penicillins

EG Amoxicillin

More effective against gram-negative bacteria

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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

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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

``` 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)