Protein Synthesis Inhibitors - Second Sessional

26/04/2022
3. Aminoglycosides 3. Aminoglycosides
 These are a group of natural (mycin) and  Source: Suffix (mycin): from Streptomyces genus bacteria
 Suffix (micin): from Micromonospora genus or semisynthetic

semisynthetic antibiotics (micin) having
polybasic amino groups linked glycosidically  Systemic aminoglycosides
to two or more aminosugar.  Streptomycin, Kanamycin, Tobramycin,

Paromomycin
 Aminosugar-O-X-O-Aminosugar
 X= a nonsugar moiety  Amikacin, Gentamicin, Sisomicin,
 Aminocyclitol i.e. 2-deoxystreptamine

Netilmicin
 In streptomycin, it is Streptidine  Topical aminoglycosides: Neomycin,

Framycetin
Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal
33 Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal
34
33 34
 Common properties of aminoglycoside antibiotics
1. All are used as sulfate salts, which are highly water  Mechanism of action
soluble; solutions are stable for months.
2. They ionize in solution; are not absorbed orally;
distribute only extracellularly; do not penetrate brain or
CSF.
3. All are excreted unchanged in urine by glomerular
filtration.
4. All are bactericidal and more active at alkaline pH.
5. They act by interfering with bacterial protein
synthesis.
6. All are active primarily against aerobic gram-negative
bacilli and do not inhibit anaerobes.
7. There is only partial cross resistance among them.
8. They have relatively narrow margin of safety.
9. All exhibit ototoxicity and nephrotoxicity.
36
35 36
26/04/2022
 Porin channelstransport into periplasmic
space  Concentration dependent killing
 Energy and O2-dependent transport across
membrane  Post-antibiotic effect
 Inactive against Anaerobic bacteria
 30S
 Misreading of genetic code
 Improper initiation complex  Antibacterial Resistance mechanism
 Movement of ribosome is blocked  Decreased transport
 Single ribosome attached with mRNA  Enzymatic inactivation
 Assembly of polysomes interfered
 Ribosomal protection
 Accumulation of non-functional ribosomes
38
37 38
 Spectrum  ADME
 G-ve aerobic bacilli…?  Highly polar basic drugs
 Poor oral BA, excreted in faeces
 A few G+ve Cocci…?  Short half life
 i.m., i.v. and topically
 Minimal distribution and metabolism
 Not active against
 90-95% i.v. dose cleared by GF in kidney
 G+ve anaerobic bacilli…?
 High urinary conc. UTI
 Urinary alkanizers increases the activity
 Gram –ve cocci…?
 Clearance directly proportional to Clcr
 Caution in renal insufficiency
40
39 40
26/04/2022
3. Aminoglycosides
 Concentration dependent killing  Adverse effects
 Nephrotoxicity
 Due to inhibition of intracellular lysosomal
PLA2 in brush border
 Single daily dosing preferred over  Lysosomal rupture, acid hydrolase and
multiple dosing except in aminoglycoside release in cytosol
 Mitochondrial degeneration and necrosis
 Ototoxicity
 Renal insufficiency
 8th cranial nerve,
 Accumulate in inner ear, vestibular and
 In combination with beta-lactam cochlear damage, vertigo, loss of balance,
antibiotics in enterococcal endocarditis hearing loss and tinnitus.
41  Worsened byDeptfurosemide, vancomycin etc.
of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal
42
41 42
 NMJ blockade  1. Streptomycin : Limited use
 More relevant in case of myasthenia  First line reserve drug against TB
gravis and in patient with skeletal muscle  2. Gentamicin : commonly used
relaxants  Once daily dose equally effective and
 Displace calcium less toxic than 8hrly dosing.
 (-) Nm receptors  Topically: cream, ointments or eye drops
 (-) Ach release from Cholinergic neurons  Burns, wound and bacterial conjunctivitis
 Not useful in presence of pus
 Inactivated by purulent exudates of wounds
 3. Sisomicin
 4. Tobramycin (less nephrotoxic*)
44
43 44
26/04/2022
 5. Netilmicin: Derivative of sisomicin  Neomycin
 Resistant to aminoglycoside-inactivating  Irrigation of urinary bladder to prevent
bacteriuria with catheter
enzymes.
 External ear and eye infection
 Lesser ototoxicity*
 Orally as preoperative intestinal antiseptic
 6. Kanamycin: Highly toxic, not used  Hepatic coma
 7. Amikacin:  Framycetin
 Less toxic derivative of kanamycin  Ointment : Skin infection, Otitis externa
 Eye drops
 Commonly used
 Resistant to inactivating enzymes  Paromomycin
 Effective against MDR TB  Orally against intestinal amoebiasis
 Spectinomycin : Not a true aminoglycoside chemically

46
45 46
MACROLIDEs and Miscellaneous Macrolides

 Macrolides and  Drugs
 Erythromycin (S. erythreus)
 Miscellaneous antibiotics  Azithromycin
Semisynthetic derivatives
 Ketolides  Roxithromycin of erythromycin
 Lincosamides
 Clarithromycin
 Oxazolidinones
 Mupirocin  Spiramycin (S. ambafaciens)
 Fusidic acid
 Streptogramins A and B
 Polymyxin B  Multimember (14 membered) lactone
ring structure, to which deoxy-sugar
molecules are attached.
48
47 48
26/04/2022
Macrolides Macrolides
 Mechanism  Mechanism of resistance
 “50s – translocation – protein synthesis”  Ribosomal protection: Due to
 Explanation??
modification of receptor site at 50S-
methylation
 Note:
 Selective toxicity to microbes  Efflux systems
 1. Do not bind to mammalian 60s or 40s
 Transport failure
 2. Do not permeate through mitochondrial
membrane of host cells
 Enterobacteriaceae - esterase
 Being weak base, their antimicrobial
activity is increased by alkaline pH
50
49 50
Macrolides Macrolides - Pharmacokinetics

 Antibacterial spectrum  Erythromycin
1. Overlapping spectrum with ampicillin
 Free base  destroyed by acidic pH
2. G+ve cocci (except resistant Staph.)
 Enteric coating / ester salts are effective
3. G-ve cocci: Neisseria, M. catarrhalis
 Food delays absorption
4. G+ve bacilli: C. tetani, B. anthracis, C.
 Erythromycin estolate: No effect of food on
diphtheriae
absorption
5. G-ve bacilli: H. influenza, H.pylori, B. pertussis
 Distribution
6. Acid fast: MAC, M. leprae (except M.
 Accumulation : Tonsills, middle year, lungs,
tuberculosis)
prostate fluid
7. Spirochetes : T. pallidum (Syphilis)
 Increased concentration in alveolar
8. Misc: M. pneumoniae, Ureaplasma, Chlamydia macrophages
 Low CSF levels
52
51 52
26/04/2022
Macrolides - Pharmacokinetics Macrolides - Pharmacokinetics

 Erythromycin (t1/2: 1.5h)  Azithromycin
 Metabolism: Liver  Acid stable
 Excretion: Bile to Faeces  Food retards absorption (administration
 (Renal failure?) 1h before or 2h after meal)
 Roxithromycin: Acid stable, No food  Wide distribution
interference, Long t1/2: 12h
 Lung, phagocytes, macrophages,
 Clarithromycin: Acid stable, No food fibroblasts, genital tissue and liver
interference, Long t1/2: 7h
 Elimination half life: 68hrs
 Spiramycin:  Post antibiotic effect
 Similar to erythromycin except half life  Excreted unchanged largely into bile
8h and secreted through breast milk
(prevent transfer of infection to infants)
54
53 54
Macrolides - Uses Macrolides - Uses

 Erythromycin  Roxithromycin
 First choice of drug for  Similar to erythromycin
 Atypical pneumonia (M. pneumoniae)  Preferred for otitis, sinusitis and pneumonia
 Diphtheria (M. catarrhalis)
 Pertussis  Clarithromycin
 Second choice  Similar to erythromycin
 Chlamydial: conjunctivitis, urethritis  Additionally : MAC, H. influenza, M. Leprae,
 Gastroenteritis H. pylori
 Other uses  Azithromycin
 Anti-inflammatory : arthritis, asthma ??  Similar to clarithromycin
 Improves gastric emptying : Motilin  More efficacious against H. influenza, M.
receptor agonism catarrhalis
56
55 56
26/04/2022
Macrolides – Adverse effects

and drug interaction Miscellaneous AMAs
1. Allergy (with Erythromycin estolate)
 Miscellaneous antibiotics
2. Hepatitis (cholestatis hepatitis, Erythromycin
estolate, jaundice, fever, eosinophilia) 1. Ketolides
3. Gastric pain : Erythromycin estolate, increased 2. Lincosamides
GI motility
3. Oxazolidinones
4. Ototoxicity
4. Mupirocin
5. Thrombophlebitis
DI: 5. Fusidic acid
1. Drug interaction due to enzyme inhibition eg. 6. Streptogramins A and B

Erythromycin and clarithromycin 7. Polymyxin B
2. Digoxin toxicity: (-) microbial flora which
degrades digoxin
58
57 58
Ketolides Ketolides
 Macrolides (with 3 keto groups in  Stronger post-antibiotic effect
erythromycin) designed for  Good oral bioavailability, Long half life
community acquired respiratory (13-14h)
infections  Accumulates in respiratory tissue and
 Telithromycin, Cethromycin (more fluids
potent)  Spectrum similar to erythromycin
 Mechanism: similar to erythromycin  but also effective against Macrolide
 But superior due to resistant cocci and bacilli
 Strong binding of drug to ribosomes  Use: Macrolide resistant community
 Decreased incidence of drug resistance
(Poor substrate for efflux pumps)
acquired pneumonia
60
59 60
26/04/2022
Lincosamides Oxazolidinones
 Lincomycin and Clindamycin  Torezolid, Linezolid, Radezolid
 Pure synthetic drugs
 Obsolete
 Linezolid : 100% oral bioavailability
 Mechanism: Similar to macrolides  MOA: 50S subunit, (-) initiation complex
 Use: Liver, lung, pelvic abscess due to required for translation, Unique mechanism
cocci and bacilli except MRSA and C. which inhibits first step of protein synthesis.
difficile, respectively  Adv. Effects: Reversible thrombocytopenia,
neutropenia (non-specific inhibition of 60S mammalian
 Adv effect: clindamycin results in ribosome subunit)
superinfection, hypersensitivity, NMJ  Reserve drug for MDR gram+ve (MRSA, SA,
S.pneumoniae, vancomycin resistant enterococcus
blockade etc.  Inhibits MAO: Cheese reaction (Hypertensive crisis)

62
61 62
Mupirocin Fusidic acid

 Topical antibiotic for burns, leg  Interferes at peptide chain elongation
ulcers, folliculitis  By inhibiting elongation factor G
 Intranasal irradication of MRSA colony  Useful for deeper skin infections such
 It inhibits RNA and protein synthesis by as boils
binding to isleucyl-tRNA synthetase  Effective against penicillinase
prevent the incorporation of isoleucine
producing bacteria (S. aureus and
into the bacterial protein
gram positive bacilli)
 Spectrum
 MRSA and other Gram+ve cocci, all other
are resistant

64
63 64
26/04/2022
Pristinamycin Polymyxin B and colistin (E)

 Very toxic peptides rarely used except topically
 Combination of 70:30 ratio
 Cationic detergent which disrupt bacterial cell membrane
 Dalfopristin (Streptogramin A) + osmotic integrity by displacing calcium and magnesium
Quinupristin (Streptogramin B) from membrane lipid phosphates.
 Thus, leads to leakage of intracellular constituents and
 Bind to 50S and inhibit the extrusion of subsequent death of bacteria.
newly synthesize peptide chain  Spectrum: G+ve bacteria, synergism with neomycin
 Resistant cases of skin infection, and bacitracin
bacteraemia, MRSA and G+ve  Used for skin, eye and ear infections
 Orally for oropharyngeal decontamination
 Very short half life (0.7hrs and 0.85hrs)
 Neurotoxicity, Nephrotoxic, NMJ blockade, Histamine
 But, prolong action due to post release (flushing and bronchoconstriction)
antibiotic effect, therefore once a day
dosing.
66
65 66
Binding sites: overview

30S : Tetracycline, Glycylcycline (Tigelcycline)
Streptomycin, [Spectinomycin (- translocation)]
50S : Aminoglycosides (Except streptomycin)
Chloramphenicol, Macrolides, Ketolides,
Lincosamides (Lincomycin and clindamycin),
Streptogramins (Pristinamycin)
Oxazolidinones
30S and 50S interface: Aminoglycosides (Except

streptomycin)
Principles of pharmacology : the pathophysiologic basis of

drug therapy / David E. Golan, 3rd ed.
68
67 68
26/04/2022
Thank you

69
69

Protein Synthesis Inhibitors - Second Sessional

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Protein Synthesis Inhibitors - Second Sessional

Uploaded by

Copyright:

Available Formats

26/04/2022

 Suffix (micin): from Micromonospora genus or semisynthetic

to two or more aminosugar.  Streptomycin, Kanamycin, Tobramycin,

 X= a nonsugar moiety  Amikacin, Gentamicin, Sisomicin,

 Aminocyclitol i.e. 2-deoxystreptamine

 In streptomycin, it is Streptidine  Topical aminoglycosides: Neomycin,

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal

MACROLIDEs and Miscellaneous Macrolides

Macrolides Macrolides - Pharmacokinetics

Macrolides - Pharmacokinetics Macrolides - Pharmacokinetics

Macrolides - Uses Macrolides - Uses

Macrolides – Adverse effects

1. Drug interaction due to enzyme inhibition eg. 6. Streptogramins A and B

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal

Mupirocin Fusidic acid

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal

Pristinamycin Polymyxin B and colistin (E)

Binding sites: overview

30S and 50S interface: Aminoglycosides (Except

Principles of pharmacology : the pathophysiologic basis of

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal

You might also like