Protein synthesis inhibitors Flashcards
Discuss the characteristics of tetracycline
- Bacteriostatic
* Basic structure and activity is common
Give the important examples of tetracycline
- doxycycline
2. minocycline
Discuss the spectrum of tetracycline
They have abroad spectrum
What are the uses of tetracycline
- Chronic bronchitis
- Tigecycline is used in tetracycline resistant bacteria
- DRUG OF CHOICE AGAINST ORGANISM ;
- Rickettsia
- chlamydia
- brucellosis
- Mycoplasma
- spirochaetal infections
Discuss the mechanism of action of tetracycline
- Enter microbe via passive diffusion and active transport in gram pos cells .
- sensitive cells concentrate the drug intracellularly
- Then binds to 30S bacterial ribosomal subunit
- Then prevents formation of initial complex
- Inhibits codon -anti codon interaction ultimately preventing insertion of new codon
Tetracyclines are crystalline amphoteric molecules(has acid and base properties ) and thus has low soluability
What can lead to resistance of tetracycline
- Decaresed intracellular accumulation(decreased influx or active efflux)
- Production of protein that interferes with the binding of tetracycline on ribosome
- Enzymatic inactivation
Discuss the pharmacodynamics of tetracycline
- Orally administered and must be taken with adequate fluid
- Antacids or milk prevent absorption because they form insoluble complexes
- Tetracycline are widely distributed eg they can cross the placenta and enter breast milk
Discuss the pharmacokinetics of doxycycline and minocycline particularly
- highly lipid soluble
- Nearly completely absorbed in the presence of food
- they are less incline to chelate
- They are mainly excreted in bile and safer in renal impairment
What are the side effects of tetracyclines ?
- Cause GIT disruption eg nausea and vomiting (dose related )
- Destruction of gut flora due to irritation of mucous membrane resulting superinfections with candida
- Pseudomembraneous colitis due clostridium difficile can also occur ( due to the antibacterial effect on gut flora )
- Causes hepatotoxic effects in elderly patients
- leads to photosensitivity
- Deposited in bone and teeth
- cause bone retardation in children
- Discolouration of nails and teeth
- Potentially nephrotoxic
- Reduced efficacy in combined oral contraceptive pill
What are the side effects of minocycline
- Blue-grey pigmentation of the skin and pigmentation of acne scare
- vestibular toxicity
What are side effects of tigecycline
increased mortality and treatment failure noted
how does tetracycline?
- Carbamazepine ,phenytoin ,barbiturates ,rifampicin (serum levels of doxycycline decreased )
- Vitam A and other retinoids enhances risk of increased intracranial pressure
- Combined oral contraceptive pill
Discuss the cautions / contraindication
- Systemic lupus erythematosus
- Myasthenia gravis
- Heptic impairment
- porphyria
- elderly
- C/I in pregnancy ,children more than 8-12 years
Discuss the chloramphenicol
- Bacteriostatic
- Broad spectrum antibiotic
- RARELY USED AS FIRSST CHOICE TREATMENT BECAUSE OF POTENTIALLY TOXICITY
- Only reserved for severe infections by susceptible organisms due to potential to cause aplastic anemia
Discuss the spectrum and uses of chloramphenicol
Used for
- rickettsia infections and meningitis
- typhoid fever
- Used for bacterial eye infection
- Must not be used for long term treatment
- nor for prophylactic uses
Discuss the spectrum of chloramphenicol
- Chlamydia and mycoplasma infections
- strep and staph cocci
- hemophilic infections
- anaerobes
Discuss the MOA of chloramphenicol
- Powerful inhibitors of protein synthesis
- Attaches to 50S ribosomal subunit
- Interferes with the MOA of peptidyltransferase
How can resistance be gain against chloramphenicol
1.Production of chloramphenicol acetyltransferase that inactivates the drug
Discuss the pharmacokinetics of chloramphenicol
- Highly soluble in water
- when orally digested it give 80% bioavailability
- It is widely distributed and occurs in high levels in brain and CFS
- 30-50% is protein bound
- half life is 1.5 - 4 hours ( It is prolonged i young children )
- It is metabolized in the liver after glucuronide formation ,it is excreted in the urine
What are the side effects of cloramphenicol -7
- Irreversible bone depression resulting in aplastic anemia ( bad for cancer patients )
- Dose-related reversible bone marrow toxicity
- efficacy is reduced when combined with contraceptive pill
- use with great care in babies ,because of ineffective conjugation with glucuronic acid ,the drug is not excreted leading to grey baby syndrome
- grey baby syndrome symptoms : abdominal distention ,cyanosis ,vasomotor collapse and failure to feed
- GIT effects ,optic and peripheral neuritis
- Hypersensitivity reaction and jaundice
- inhibits liver enzymes
How does chloramphenicol interact with other drugs ?
- Causes hepatic enzyme inhibition thus increase concentrations of phenytoin ,warfarin
- Used with hepatic enzymes inducers ,resulting in efficacy of chloramphenicol
- When combined with vit b ,folic acid and iron ,it may interfere with homological response
- Combined with oral contraceptive pill
What are the Cautions/Contraindication of chloramphenicol
C/I : – Allergy – Porphyria – Third trimester of pregnancy – Neonates – Lactation Caution: – Impaired hepatic function – Bone marrow depression
Discuss the characteristics of clindamycin
- attacks susceptible gram pos infections in patients with allergic to penicillin
- Sensitive staphylococcal and anaerobic infections
- Used for severe soft tissue infections
- lung abscesses
- quinsy
- inactive against enterococci
- bacteriostatic but bactericidal at high concentrations
Clindamycin MOA
- Similar mechanism to action of macrolides and the binding site is similar to macrolides
- It inhibits the 50S subunit of bacterial ribosomes
- interferes with formation of initial complex
- inhibits translocation
How can resistance be developed against clindamycin
- Mutation of binding site
* Enzymatic inactivation
Discuss the pharmacokinetics of clindamycin
- Can be well absorbed with oral ,IM or IV administration
- Must be taken with enough water
- Widely distributed except for CSF
- half life is 2-3 hrs and it is prolonged in hepatic and renal diseased patients
- it is excreted in bile
- 10% in urine
Discuss the side effects of clindamycin - 5
- Diarrhea ,nausea and skin reaction
- Transient increase in liver enzymes and bilirubin
- temporary leucopenia ,thrombocytopenia ,eosinophilia
- Pseudomembranous colitis : caused by clostridium difficile
- Affected by contraceptive pill
How does clindamycin interact with other drugs
Oral contraceptive
Cautions in clindamycin
1.GIT disease
*severe hepatic impairment
*porphyria
elderly
pregnancy / lactation
Discuss the use and spectrum of fusidic acid
- steroid antibiotics
- can be used for staph infections eg oseomyelitis ,pneumonia and septicaemia
- Combination with another anti-staphylococcal agent to prevent emergence of resistance
Development of resistance of fusidic acid
- inhibiting translocation
* used for skin infection for 5 days and conjunctivitis
Discuss the pharmacokinetics of fusidic acid
- Readily absorbed orally
- widely distributed except for CSF
- Penetrates into bone very well
- 95% plasma protein bound
- half life is 5-6 hrs
- can be excreted in faces
- can be administered topically
What are the side effects of fusidic acids
- hepatoxicity
- avoid in pregnancy
- IM- local tissue necrosis
- local hypersensitivity
- risk of kernicterus in neonates
contraindications
*hepatic disfunction
Mupirocin
Spectrum
Spectrum: Gram pos. bacteria, effective against
methicillin-resistant Staphylococcus aureus
Mupirocin Mechanism of action:
Inhibits protein and RNA synthesis also DNA
and cell wall synthesis
– Bactericidal
Mupirocin
Pharmacokinetics:
Rapidly inactivated after absorption
– No systemic absorption
– Topical application only (topical & intranasal)
– Preparations contains polyethylene glycol,
may lead to toxicity
Side-effects: Mupirocin
Mild stinging, burning, itching at site of
application
Caution: porphyria
Ketolides
Semi-synthetic derivatives of erythromycin A →
broader spectrum
• Telithromycin
• Spectrum/Uses
– Similar spectrum to macrolides, H. influenzae
– Erythromycin–resistant strains of
pneumococcus
Ketolides• Mechanism of action
• Mechanism of action
– Can bind to 2 sites on the bacterial ribosome,
with higher affinity than macrolides
Ketolides
• Pharmacokinetics
Once daily dosing → 5 days
– Metabolised in liver, Excretion: biliary and
urinary
Ketolides Side effects
- Inhibits liver enzymes
2.Risk of potentially serious hepatotoxicity
3.Respiratory failure → myasthenia gravis
patients
4.Visual disturbances
5.Loss of consciousness
Oxazolidinones uses
Gram positive bacteria – Cloxacillin-resistant staphylococci & vancomycin-resistant enterococci, MRSA – Mostly bacteriostatic – Bactericidal against streptococci – Drug resistant M. tuberculosis
Oxazolidinones
• Mechanism of action
Prevents the formation of the ribosome complex
– Binds to 23S ribosomal RNA of the 50S
ribosomal subunit inhibits protein synthesis
• Pharmacokinetics of Oxazolidinones
IV or oral (100% bioavailability)
– Metabolised, yield 2 inactive metabolites
– Non-renal clearance is approx. 65% of total
Oxazolidinones
• Side-effects
Oxazolidinones
• Side-effects
Lipopeptides
• Daptomycin in clinical use (IV)
• Naturally occurring compound found in soil Streptomyces
roseosporus
• Spectrum/Uses:
– Infections caused by multi-resistant bacteria
– Active against Gram pos. bacteria only
– S. aureus bacteraemia incl. right-sided infective
endocarditis
– Disrupting bacterial cell membrane function
– Inhibition of protein, DNA and RNA synthesis
– Large number of side effects (myopathy)
