Protein Synthesis Inhibitors II Flashcards
Name the tetracyclines
TDM
Tetracycline
Doxycycline
Minocycline
Lymecycline
Oxytetracyline
What are Tetracycilnes
are crystalline Amphoteric molecules with low solubility: have an acidic and basic functional group–> not soluble
Name the a new drug class derived from Minocycline
Glycylcyclines
Name a Glycylcycline
Tigecycline: IV
Use of Tigecycline
treatment of resistant infections where tetracyclines on their own aren’t enough
Complicated skin, soft tissue, intr-abdominal infections
Uses of Tetracycline
Combination with other agents for treatment of Malaria
DOC in: Rickettsia
Chlamydia
Brucellosis
Mycoplasma infections
Spirochetal infections
Acne: due to its good skin penetrability
Chronic Bronchitis
Doxycyline uses
Prophylaxis of malaria
MOA of Tetracyclines
Bind to 30S subunit–> prevents formation of initiation complex=inhibits codon-anticodon interactions
How do the Tetracyclines enter the cell
move into micro-organisms via passive diffusion through the porins and energy dependent process of active transport
Resistance mechanisms against Tetracyclines
- Decr. intracellular accumulation as a result of decr. influx or active efflux (production of active Efflux pump that pumps the Tetracyclines out of the cell)
- Production of protein that interferes with the binding of Tetracyclines on Ribosome
- Enzymatic inactivation of drug
Admin of Tetracyclines
Orally with variable absorption
*taken with adequate amount of fluid
*Avoid antacids or milk as it prevents their absorption
Why is adequate fluid intake needed with Tetracyclines
to prevent drug capsules from sticking to bottom of Esophagus on mucosal lining=ulceration and pain
*need to remain upright for at least 30mins to prevent occurrence of Ulceration
PK benefits of newer Tetracyclines
Doxycycline and Minocycline
1. more lipid soluble–> near complete absorption in the presence of food
2. less incline to chelate
How do Antacids prevent the absorption of Tetracyclines
They contain Multivalet cations that form insoluble complexes with the Tetracyclins
Distribution of Tetracyclines
widely distributed
*cross placenta and excreted in breast milk
Excretion of newer Tetracyclines
mainly in bile thus its safer for renally impaired people
SEs of Tetracylcines
Cause GIT disruptions: dose-related NV
2. Destruction of normal gut flora=superinfections with Candida
3. Pseudomembranous Colitis: C.difficile can occure
4. Elderly patients: hepatotoxic effects
5. Photsensitivity
6. Deposited in bone and teeth: esp. young children
7. Causes bone growth retardation in children
8. Discolouration of nails+teeth and occasion Enamel Hypoplasia in kids
9. Potentially nephrotoxic effects
10. Reduced efficacy of COC
SEs of Minocycline
Blue-grey pigmentation of skin and pigmentation of acne scars
Vestibular toxicity
SEs of Tiglecycline
Incr. mortality and treatment failure seen
DIs with Tetracyclines
- CYP450 induces like Carbamazepine, phenytoin, barbiturates
- Vit A and other Retinoids: enhanced risk of incr. intracranial Pressure
- COC
Cautions of Tetracylcines
SLE: Minocycline
Myasthenia Graves: have weak neuromuscular blocking effects
Hepatic impairment
Porphyria
Elderly
CIs of Tetracyclines
Pregnancy
Children <8-12 yrs`
What is Chloramphenicol
Broad spectrum Bacteriostatic antibiotic
When is Chloramphenicol used as 1st line drug
rarely because of its potential toxicity: depresses bone marrow
Chloramphenicol is reserved for
severe infections by susceptible organisms due to potential to cause aplastic anemia
Spectrum/Uses of Chloramphenicol
Rickettsial infections: standard drugs CIed
Bacterial meningits: standard drugs CIed
Typhoid fever
Bacterial eye infections: topical
Chloramphenicol is active against
Chlamydia
Mycoplasma infections
Streptococci
Staphylococci
Hemophilus infections
Anaerobes
MOA of Chloramphenicol
powerful inhibitor of Protein Synthesis
Attaches reversibly to 50S subunit–> interferes with MOA of Peptidyl transferases
MOA of Peptidyltransferase
catalyses formation of peptide bind btwn growing peptide and new AA
=peptide cant grow further
Resistance mechanism against Chloramphenicol
Production of Chloramphenicol Acetyltransferase that inactivates the drug
Admin of Chloramphenicol
Chloramphenicol succinate: parenteral
–> highly water soluble where it gets hydrolysed to free Chloramphenicol
Distribution of Chloramphenicol
widely distributed
*high levels in brain and CSF: effective against meningitis
Metabolism of Chloramphenicol
in liver and after Glucuronide formation its excreted in urine
SEs of Chloramphenicol
- Serious IRREVERSIBLE Bone Marrow Depression–> idiosyncratic–> fatal aplastic anemia (esp. topical use)
- Dose-related reversible Bone Marrow Toxicity
- Reduced Efficacy of COC
- Use with great care in babies as ineffective conjugation with Glucuronic acid and excretion of drug cause: GREY BABY SYNDROME
- GIT effects
- Optic or peripheral neuritis
- Hypersensitivity rxns and jaundice
- Inhibits liver enzymes
GREY BABY SYNDROME is characterised by
abdominal distention
cyanosis
vasomotor collapse
Failure to feed
DIs with Chloramphenicol
- Causes CYP450 Inhibition: incr. conc. of Phenytoin, warfarin, sulfonylureases
- CYP450 inducers: decr. efficacy of Chloramphenicol
- Vit B, folic acid and iron: Chloramphenicol may interfere with Hematological response
- COC
Cautions in Chloramphenicol
Impaired hepatic function
Bone marrow depression: cancer, HIV patients
CIs of Chloramphenicol
Allergy
Porphyria
3rd trimester of pregnancy
Neonates
Lactation
Spectrum/Uses of Clindamycin
Susceptible gram +ive infections in patients allergic to Penicillins
Susceptible Staphylococcal and Anaerobic infections
Severe soft tissue infections
Lung Abscesses
Quinsy: not responding to Penicillins
Clindamycin is inactive against
Enterococci
MOA of Clindamycin
Inhibits protein synthesis by:
binds to 50S subunit–> interferes with formation of initiation complex–> inhibits translocations
Different dosages of Clindamycin cause
Low: Bacteriostatic
High: Bactericidal
Resistance mechanisms against Clindamycin
Mutation of ribosomal binding site
enzymatic inactivation
Admin of Clindamycin
Oral, IV, IM
*taken with adequate fluid to prevent ulceration
Metabolism and Excretion of Clindamycin
M; liver
E: mainly in bile, small unaltered amount in urine
Distribution of Clindamycin
widely distributed
*doesn’t enter CSF
SEs of Clindamycin
ND: oral, IV,IM
skin rxns
Transient incr. in liver enzymes+bilirubin
Transient Leucopenia, Thrombocytopenia, Agranulocytosis, Eosinophilia
Pseudomembranous Colitis: potentially fatal complication
Reduced efficacy of COC
DIs with Clindamycin
COC
Caution in Clindamycin
GIT disease
severe hepatic impairment
porphyria
elderly
pregnancy/lactation
What is Fusidic Acid
Steroid antibiotic thats usually given Orally/Topically
Spectrum/Uses of Fusidic Acid
Severe Staphylococcal infections
Combine with Cloxacillin (antistaphylococcal) to prevent emergence of resistance
Topically: acute skin infections (5days) and conjunctivis
SEs of Fusidic Acid
Reversible Hepatotoxicty
GIT effects: take with meals
Kernicterus risk in Neonates
AVoid in Pregnancy
IM: local tissue necrosis
Local Hypersensitivity rxns
DIs of Fusidic acid
Hydrocortisone: decr. Antibiotic activity and reduced efficacy of Fusidic acid
Statins: incr. risk of Rhabdomyolysis
CIs of Fusidic Acid
Hepatic Dysfunction: as its excretd in bile
Spectrum of Mupirocin
Gram +ive ONLY
Effective against Methicillin-resistant Stapylococcal aureus (MRSA)
MOA of Mupirocin
Reversibly binds to Isoleusine-tRNA Synthetase and prevents formation of Isoleusine-tRNA
–>inhibits protein and RNA synthesis
High dosages of Mupirocin results
in Bactericidal effects
Admin of Mupirocin
Topical only + intranasal
*rapidly inactivated after absorption if given orally
SEs of Mupirocin
Mild stinging
Burning
Itching at site of application
Caution in Mupirocin
Porphyria
What are Ketolides
Semi-synthetic deruvatives of Erythromycin A–> have broader Spectrum
Name a Ketolide
Telithromycin
Spectrum/Uses of Ketolides
similar spectrum to macrolides, H.influenzae
Erythromycin-resistant strains of Pneumoccoccus
MOA of ketolides
Can bind to 2 sites on bacterial ribosome with higher affinity than macrolides
*may inhibit formation of newly forming Ribosomes
SEs of Ketolides
Inhibit Liver Enzymes
Serious Potential Hepatotoxic risk
Respiratory failure in Myasthenia Gravis patients
Visual disturbance
Loss of Consiousness
When are Ketolides used
ONLY WHEN NEEDED
Serious infections that dont respond to anything
What are Oxazolidinones
New class of Synthetic antibiotics
Name an Oxazolidinones
Linezolid
Spectrum/Uses of Oxazolidnones
Gram +ive bacteria (staphylococci, streptococci, enterococci, Gram +ve Anaerobic cocci and Rods)
Cloxacillin-resistant Staphylococci and Vancomycin-Resistant Enterococci, MRSA
Drug resistant M.Tuberculosis
Are Oxazolidinones Bacteriostatic or Bactericidal
Mostly bacteriostatic
*Bactericidal against Streptococci
When should the Oxazolidinones be used
As last resort where other Antibiotic therapy has failed–> should be reserved for this purpose
MOA of Oxazolidinones
Prevents formation of Ribosomal COmplex
Binds to 23S subunit of 50S subunit =inhibits Protein Synthesis
Admin of Oxazolidinones
IV or oral, 100% bioavailable
Resistance mechanism against Oxazolidinones
Mutation of Linezolid binding site on 23S ribosomal subunit
SEs of Oxazolidinones
Hemolytic toxicity: mild & reversible
Peripheral Neuropathy: prolonged use
Reversible non-selective inhibitor of MAO
Headache
Moniliasis/fungal infection
Metalic taste
GIT effects
Neurotoxicity
DIs of Oxazolidinones
Sympathomimetic or Adrenergic drugs
–>produce Serotonin Syndrome: fever, flushing, sweating, tremors, delirium
What are Streptogramins
Semisynthetic derivatives of Pristinamycin: which is a naturally occurring STreptogramin
Name the Streptogramins
Quinupristin-Dalfopristin: fixed 30/70
Effect of combined Streptogramins
Synergistic
Each agent alone: bacteriostatic
Combined: Bactericidal
Spectrum/uses of Streptogramins
Most Gram +ive bacteria and most respiratory pathohens
90% Stap. aureusa and Coagulase neg. Staphylococci incl MR strains
Penicillin resistanct Pneumococci
Enterococcus Faecium incl. strains which are resistant to Ampicillin, Genatmicin and Vancomycin
MOA of Streptogramins
bind to distant sites o 50S subunit–> interfere with Peptidyl Transferase enzyme
Resistance mechanism against Quinuprostin
- A ribosomal methylase that prevents binding
- Lactonase produced that inactivates the drug
Resistance Mechanisms against Dalfopristin
Acetyltransferase produced that inactivates drug
–> incr. efflux of drug
Admin of Streptogramins
IV: rapid metabolism
Effect of Streptogramins on Liver enzymes
inhibit CYP3A4–> DIs
SEs of Streptogramins
Inflammation, pain, Oedema, infusion site rxn, Thromophlebitis
NVD
Rash, purirtis
Headache
Pain
Athralgia and Myalgia
Asthenia
Conjugated Hyperbilirubinaemia
DIs of Streptogramins
Warfarin
Diazepam
Terfenadine
Astemiazole
Cisapride
NNRTI
Cyclosporine
–> inhibition of their metabolism
What is a Lipopeptide
naturally occurring compound found in soil of Streptomyces Roseosporus
Name a Lipopeptide
Daptomycin: IV
Spectrum/Uses
infections caused by multi resistant bacteria
Active against Gram +ive bacteria only
MRSA
Glycopeptide Resistant enterococci
Skin and skin structures infections: gram +ive
S.aureus bacteriaemia incl. right-sided infective Endocarditis
MOA of Lipopeptides
Disrupting bacterial cell membrane function
Bind to membane and cause rapid depolarisation
Cause a loss of membrane potential
inhibition of protein, DNA and RNA synthesis
Bactericidal: depends on conc.
SEs of Lipopeptides
CVS, CNS SEs
Rash
GIT effects
Electrolyte disturbance
Hematological, musculoskeletal and hepatic effects
Hypersensitivity rxns
Possible myopathy and Rhabdomyolysis with statins
Drugs that cause Disruption of Bacterial Plasma Membrane
Polymyxin B and E(Colistin)
MOA of Polymyxin B and E
attach to Phospholipids in bacterial plasma membrane–> disrupt membrane structure
Change membrane permeability
Selective bactericidal to Gram -ive bacteria
Admin of Polymyxin B
Topical use only in combination with other agents
Spectrum/Uses of Polymyxin B
Skin, eye, ear infections
When is IV Polymyxin used
combination salvage therapy in exceptional cases of infections due to multi-drug resistant gram -ive pathogens (p.aeuroginosa, Actinobacter baumanii)
SEs of Polymyxin
Parentral: nephrotoxic and neurotoxic
Admin of Polymyxin E(colistin)
IV, combination therapy
Spectrum/Uses of Colistin
Severe Resistant Gram -ive infections (carbapenems resistant)
Last line treatment for Multi-drug resistant infections
SEs of Colistin
Reversible Nephrotoxicty
