39. Antibiotics Flashcards
Why with developing antimicrobial resistance do we not make new antibiotics?
- number of antibioitcs reaching market has dropped hugely over past 10 years
- resistance reduces effective life of a product
- too little profit, government restrictions, lack of new biological targets
3 antibiotic modes of action
- bactericidal
- bacteriostatic
- bacteriolytic
Explain bacteriostatic antibiotics
- hold everything in steady growth state
- total cells stays the same over time and so does viable cells
Explain bacteriocidal antibiotics
- after addition of it, number of viable cells rapidly decreases
- total number of cells stays the same
Explain bacteriolytic antibiotics
- both total and viable cells decrease drastically in numbers
- kills bad and normal cells
Common bacterial targets for antibiotics are …
- cell membrane
- cell wall
- protein synthesis
- RNA polymerase
- DNA synthesis
- folate metabolism
Penicillins target what?
cell wall
Sulphonamides target what?
folate metabolism
Fluroquinolones target what?
DNA synthesis
Macrolides target what?
protein synthesis
Tetracycline target what?
protein synthesis
Why do antibiotics target what they do?
- unique components to invading organism
- non toxic to host (relatively)
Structure of penicillins
- beta lactam ring
- a lactam is a cyclic amide
- a beta-lactam is a lactam with a heteroatomic ring structure, consisting of 3 carbon atoms and 1 nitrogen atom
List types of penicillins
- benzylpenicillin
- beta-lactamase-resistant forms e.g flucloxacillin
- broad-spectrum penicillins e.g amoxicillin
- extended-spectrum penicillins
- reversed-spectrum penicillins
Benzylpenicillin are the … form and not very active against …
- original
- gram negatives
Explain early penicillins
- acid labile
- given orally (not very well absorbed) or parenteral route (slow IV, preverable IM, high availability)
- narrow spectrum of activity - gram positives but only a few gram negs
Main difference between benzylpenicillin and broad-spectrum penicillins
- broad spec more effective against gram negative bacteria
Penicllin development
- needed derivatives of penicillin which could treat a wider range of infections
- offered a broader spectrum of activity than original penicillins e.g ampicillin
- amino group facilitates penetration of outer membrane of gram neg bacteria
- further development led to amoxicillin with improved duration of action
- much better absorption profile
Beta-lactamase-resistant forms are important against …
beta-lactamase producing bacteria
Extended spectrum penicillins are important against …
pseudomonads
Reversed spectrum penicillins have greater activity against …
gram neg than gram pos
Why is beta lactamase bad for penicillin?
- defence mechanism from bacteria
- breaks down lactam ring so antibiotic can’t act
How does a penicillin target the cell wall?
- penicillins - beta-lactam antibiotics
- inhibit the enzyme (transpeptidases) which are responsible for reaction to establish cross links in peptidoglycan cell wall
- bacteria swell and rupture
- only effective against multiplying organisms
How are bacterial cell walls strong?
- complex polymer peptidoglycan forms straight chains cross-linked together
- made of N-acetylglucosamine and N-Acetylmuramic acid
Absorption of penicillin
- vary when given orally
- delayed release preparations available (procaine and benzanthine)
Distribution of penicillin
- widely distributed in body
- although concentrations in tissues and body fluids vary
- don’t normally enter CSF (except with meninges inflammation)
Metabolism of penicillin
short half life (30-80 minutes)
Excretion of penicillin
- mainly through kidney with 90% excreted by tubular secretion
- clearance reduced in neonates
- reduce excretion rate by use of probenecid, which inhibits tubular secretion
Adverse reactions to penicillins
- hypersensitivity (seen with all penicillins, rash, fever, anaphylactic shock, serum sickness, 10-15% will show repeat reaction)
- GIT disturbance (altered gut flora)
- haemostatic effects - blood clotting
Give chain of folate biosynthesis
- pABA with dihydropteroate forms folate
- folate with dihydrofolate forms tetrahydrofolate
- goes to synthesis of thymidylate etc to form DNA
How does sulphonamide work?
- not used in clinical practice
- target metabolism
- PABA precursor to folic acid - sulphonamides are a derivative of PABA, look similar sturcturally
- can bind to same enxymes in synthetic pathway and stop it from working
- work specifically on dihydropteroate whereas trimethoprim (a type of sul) works on dihydrofolate reductase
Is sulphonamide selective?
- bacteriostatic in nature
- stops folic acid entering the bacterial cell
Absorption of sulphonamide
- 80-100% of drug given orally is absorbed from stomach and intestines
Distribution of sulphonamide
- widely distributed including CNS
Metabolism of sulphonamide
occurs in liver by n-acetylation
Excretion of sulphonamides
- in urine after around 30 minutes
Adverse reactions to sulphonamide
- photosensitivity
- Stevens-Johnson syndrome (less than 1% frequency)
- hemopoietic disturbances
Explain fluoroquinolones
- broad spectrum
- effective against Gram pos and neg
- discovered during search for antimalarial drugs
- targets DNA replication via type II topoisomerases
What do quinolones typically inhibit?
- DNA-gyrase in Gram negatives
- topisomerase in Gram-positives
What does DNA-gyrase do?
- regulates amount of supercoiling
- facilitates movement of transcription and replication complexes through DNA helix
- removes knots and helps fold DNA
What does DNA topoisomerase IV?
- homologue of gyrase
- unlinks daughter DNA replicons
Absorption of quinolones
oral admin more effective
Distribution of quinolones
- very well absorbed in upper GIT
Metabolism of quinolones
potent inhibitor of CYP1A2
Excretion of quinolones
mainly excreted in tubular secretion
Adverse reactions to quinolones
- hypersensitivity
- GIT disturbance
Explain prokaryotic ribosomes
- 70S size
- 50S comprises 2 subunits of 23S and 5S
- 50S is the main site of protein synthesis
Action of macrolides
- block translocation of newly forming peptide
- binds to site near RNA exit tunnel
- causes peptidyl-transferase RNA drop off
Absorption of macrolides
- oral admin requires protected tablets
- to avoid inactivation by gastric juice
Distribution of macrolides
- diffuses readily into most tissues
- doesn’t cross blood brain barrier
- does cross placenta
Metabolism of macrolide
- metabolised by demethylation (CYP3A4)
- can potentiate effects of other drugs
Macrolides are excreted in …
bile
Adverse reactions to macrolides
- cholestatic hepatitis can occur after prolonged use of erythromycin estolate
- GIT disturbances at large dose
- transitory auditory impairment
- hypersensitivity
How do tetracyclines work?
- interrupts elongation phase of synthesis
- several binding sites on 30S RNA subunit
- sterically inhibits transfer RNA binding - unbinds, rebinds, futile loop
Absorption of tetracyclines
- greater in fasting state
- inhibited in concurrent ingestion of dairy products, metal ions, certain antacids
Distribution of tetracyclines
widely
- enters most tissues
Metabolism of of tetracyclines
- relatively long half lifes (6-18 hrs) due to enterohepatic recirculation
Excretion of tetracyclines
via both bile and kidneys via glomerular filtration
List types of antibiotics
- penicillin
- sulphonamides
- fluoroquinolones
- macrolides
- tetracyclines
