pharmacology - Protein Synthesis Inhibitors

year 1 pharmacology

Penicillin Thiazolidine & Beta-Lactam
PK Pen G -cant give orally (acid labile)
-don’t cross bbb
PK Penicillin V Oral form of natural penicillin 1)Narrow
* Natural Penicillin:
- Pen G (parenteral)
- Pen V (oral)
* Beta-lactamase
resistance penicillin:
- Flucloxacillin
2) Broad - Amoxicillin Ampicillin (lwn HELPS)
3) Extended - Ticarcillin
- Interfere with the synthesis of the bacterial cell wall peptidoglycan.
- Binds to Penicillin Binding Proteins (PBPs)
- inhibiting the cross-linking of the peptide side chains (transpeptidation reaction)
- autolysins activity Beta-lactamase enzymes, altered PBPs, change in porins duration of action Short-acting penicillin (2-6 hrs) Benzylpenicillin (Pen G)
Intermediate-acting (8-12 hrs)
-Amoxycillin
Long-acting Penicillin (>24 hrs)
Procaine penicillin Benzathine penicillin (10 days)
- Penicillin G (IV) active against (+) Streptococcal, Pneumococcal infections ,Trepanoma Pallidum (Syphilis)
Less active against (-) Gonorrhoea
Aminopenicillins
Sinusitis & some gram (-) eg ecoli
Broad penicillin – HELPS
H.influenza, E.coli, Listeria, Proteus mirabilis, Streptococcus
Hypersensitivity reactions (allergy), GI disturbances
Cephalosporin Dihydrothiazine & Beta-Lactam
PK oral/parenteral Billiary excretion only ceftriaxone. Broad spectrum Similar to Penicillin, inhibits cell wall synthesis. They are more resistant than penicillin to certain beta-lactamase. Beta-lactamase enzymes (varies by generation) Cefazolin (1st gen), Cefuroxime (2nd gen), Ceftriaxone (3rd gen), Cefepime (4th gen)
Smakin ↑ gen,
1. ↑ in activity against gram-negative bacteria
2. ↑ resistance to destruction by beta-lactamases
3. ↑ ability to reach the cerebrospinal fluid (CSF). 1st gen act as Penicillin G substitute.
Very active against Gm(+ve)
-SSP
Mildly active against Gm(-ve)
-(P Ec K)
use in surgical prophylaxis
2nd gen
More activity against Gm(-ve)
(HEN + P Ec K)
activity against Gm(+ve) -weaker eg Streptococci
3rd gen
Very active against Gm(-ve)
can cross bbb
4th gen (most give parental)
Very active against Gm(+ve) and Gm (- ve) organisms. Hypersensitivity reactions, Opportunistic infections
Monobactams None (unique) & Beta-Lactam
PK
Given I.V or I.M Narrow (Gram -ve) Binds to PBP3 inhibiting cell wall synthesis Resistant to most Beta-lactamases Aztreonam Active only against Gr negative organisms
- Pseudomonas aeruginosa infections GI upset, Superinfection,
vertigo

No cross-hypersensitivity reaction between penicillins and aztreonam
Carbapenems None & Beta-Lactam
PK
IV. Broad (Gram +ve, -ve & anaerobes) Binds to PBPs inhibiting cell wall synthesis Low susceptibility to Beta-lactamases Imipenem, Meropenem Severe life-threatening infections Nephrotoxicity (Imipenem)

1. cell wall
inhibitors
Ring Structure & PK Spectrum of Activity Mechanism of action Resistance
Mechanisms
Examples Clinical Uses Adverse Effects
Penicillin Thiazolidine & Beta-
Lactam
PK Pen G -cant
give orally (acid labile)
-don’t cross bbb
PK Penicillin V Oral
form of natural
penicillin
1)Narrow
* Natural Penicillin:
- Pen G (parenteral)
- Pen V (oral)
* Beta-lactamase
resistance penicillin:
- Flucloxacillin
2) Broad - Amoxicillin
Ampicillin
(lwn HELPS)
3) Extended -
Ticarcillin

- Interfere with the
synthesis of the bacterial
cell wall peptidoglycan.
- Binds to Penicillin Binding
Proteins (PBPs)
- inhibiting the cross-linking
of the peptide side chains
(transpeptidation reaction)
- autolysins activity
Beta-lactamase
enzymes,
altered PBPs,
change in porins
duration of action
Short-acting penicillin (2-6
hrs)
Benzylpenicillin (Pen G)
Intermediate-acting (8-12
hrs)
-Amoxycillin
Long-acting Penicillin (>24
hrs)
Procaine penicillin
Benzathine penicillin (10 days)

- Penicillin G (IV)
active against (+)
Streptococcal, Pneumococcal
infections ,Trepanoma Pallidum
(Syphilis)
Less active against (-)
Gonorrhoea
Aminopenicillins
Sinusitis & some gram (-) eg ecoli
Broad penicillin – HELPS
H.influenza, E.coli, Listeria,
Proteus mirabilis, Streptococcus

Hypersensitivity
reactions (allergy), GI
disturbances
Cephalosporin Dihydrothiazine &
Beta-Lactam
PK
oral/parenteral
Billiary excretion only
ceftriaxone.
Broad spectrum Similar to Penicillin,
inhibits cell wall synthesis.
They are more resistant
than penicillin to certain
beta-lactamase.
Beta-lactamase
enzymes (varies
by generation)
Cefazolin (1st gen),
Cefuroxime (2nd gen),
Ceftriaxone (3rd gen),
Cefepime (4th gen)
Smakin ↑ gen,
1. ↑ in activity against gram-
negative bacteria
2. ↑ resistance to destruction
by beta-lactamases
3. ↑ ability to reach the
cerebrospinal fluid (CSF).
1st gen
act as Penicillin G substitute.
Very active against Gm(+ve)
-SSP
Mildly active against Gm(-ve)
-(P Ec K)
use in surgical prophylaxis
2nd gen
More activity against Gm(-ve)
(HEN + P Ec K)
activity against Gm(+ve)
-weaker eg Streptococci
3rd gen
Very active against Gm(-ve)
can cross bbb
4th gen (most give parental)
Very active against Gm(+ve)
and Gm (- ve) organisms.
Hypersensitivity
reactions,
Opportunistic
infections
Monobactams None (unique) & Beta-
Lactam
PK
Given I.V or I.M
Narrow (Gram -ve) Binds to PBP3 inhibiting
cell wall synthesis
Resistant to most
Beta-lactamases
Aztreonam Active only against Gr
negative organisms
- Pseudomonas aeruginosa
infections
GI upset,
Superinfection,
vertigo

No cross-
hypersensitivity
reaction between
penicillins and
aztreonam

2. Carbapenems None & Beta-Lactam
PK
IV.
Broad (Gram +ve, -ve
& anaerobes)
Binds to PBPs inhibiting
cell wall synthesis
Low susceptibility
to Beta-
lactamases
Imipenem, Meropenem Severe life-threatening
infections
Nephrotoxicity
(Imipenem)
Other
Anbiotics
( eg:
Vancomycin)
Glycopeptide (unique) Narrow (Gram +ve)




Inhibits cell wall synthesis
by binding to D-Ala-D-Ala
of peptidoglycan
-leads to inhibition of
transglycosilation and thus
prevents the
peptidoglycan chain
elongation leading to
inhibition of cross linking
of the peptidoglycan
chains.
replacement of
the terminal D-
Ala by D-Lactate.
-Occurs in strains
of enterococci
and staphylococci
(VRE and VRSA)
- decreased
affinity of
vancomycin for
the binding site.
Used against MRSA (methicilin
resistant Staph aureus)
C. Difficile colitis (oral),
Serious infections by resistant
Gram +ve
Nephrotoxicity,
Ototoxicity

3. Ph 18 Protein Synthesis Inhibitors
Protein Synthesis
Inhibitors
Pharmacokinetics Mechanism of Action Resistance Mechanism Clinical Uses Adverse Effects

AmiNOglycosides**
(ATS)

Gentamicin T,P
Amikacin- P
Kanamycin -P
Neomycin – O,T
Streptomycin-P
Tobramycin -P
Paromomycin-P
Netilmicin- P


-Poorly absorbed orally,
used
parenterally(i.m,i.v)
-limited tissue
distribution
-Excreted unchanged by
the kidney


Binds to 30S ribosomal
subunit, causing
misreading of mRNA
and abnormal protein
production
Production of inactivating enzymes
(group transferases); decreased
permeation
eg. Streptococci and enterococci

gentamycin & tobramycin
(Topical)
- conjunctivitis due to GNB.

Spectinomycin: TB, gonorrhea
(backup)



Nephrotoxicity,
Ototoxicity,
neuromuscular
blockade,
hypersensitivity
reactions
Netilmycin & amikancin : Relatively
resistant to inactivation by bacterial
enzymes
Tetracyclines**

• Short-acting :
Tetracycline,
Oxytetracycline
• Intermediate-acting:
Demeclocycline,
Methocycline
• Long-acting :
Doxycycline,
Minocycline
Well absorbed orally,
distributed widely in
tissues (oral,IV,topical)
Binds to 30S subunit,
inhibiting the
attachment of tRNA to
the ribosome
-Efflux pumps
-Decreased activity of the uptake
systems
Primary uses: cholera,
plague, brucellosis
Secondary uses: syphilis, acne

Doxycycline used to treat
periodontal disease and
prostatitis
-superinfection
-irritate GI tract.
-Hepatic, Renal,
Vestibular toxicity.
-photosensitivity,

pregnant women and
children below 14:
enamel dysplasia &
retardation of bone
growth
Spectinomycin Binds to 30S ribosomal
subunit
Principal use is anogenital
gonorrhea in patients
who cannot tolerate
ceftriaxone.
Urticaria, dizziness,
nausea, chills, fever,
insomnia.

4. Chloramphenicol
(CELLS)
Broad spectrum
antibiotic and
bacteriostatic.
Sensitive to a large
number of GPB & GNB.
Very good
action against
Salmonella typhi
Binds to 50S ribosomal
subunit,
Block transpeptidation
and
prevents protein
synthesis
Meningitis,
brain abscesses,
alternative cephalosporin
fatal aplastic anemia,
grey baby syndrome,
hypersensitive
Macrolides**
(ECAT)
Erythromycin
Clarithromycin
Azithromycin
Telithromycin


Azithromycin:
• has a similar spectrum to
erythromycin but is more
active against Chlamydia,( co-
DOC), infection with
Gonorrhea – (single dose ) ,
Toxoplasma and
Mycobacterium avium
complex (MAC)
• Safe in pregnancy

Clarithromycin:
• approved for prophylaxis of
MAC and in H. pylori
regimen.
• Inhibits P 450 and causes
reversible deafness in high
dose
Binds to 50S subunit,
inhibiting the
polypeptide chain
elongation & protein
synthesis
In GPB:
-the efflux pump
-production of methylase enzyme
Enterobacteriaceae:
-formation of drug metabolising
esterases

Cross-resistance with other macrolides
**-patients who are allergic
to penicillins.
– legionnaire's disease
(Legionella pneumophilia)
– diphtheria (C. diphtheriae),
-DOC for community acquired
pneumonia
(Mycoplasma/Legionella/
Chlamydia)- atypical bacteria
GI disturbances
(epigastric pain nausea,
vomiting,
diarrhea).

inhibitors of
cytochrome p450
system(Erythromycin
and Clarithromycin)**
Lincosamides
Lincomycin
Clindamycin
Clindamycin:
Narrow spectrum
Same as macrolides Methylation of ribosomal binding site Anaerobic infectiaons,
prophylaxis for endocarditis in
penicillin-allergic patients
-superinfection due to
C. difficile
-hypersensitivity
reactions
-Contraindicated with
erythromycin &
chloramphenicol

5. Linezolid
(Oxazolidinones)**
Bacteriostatic; active
against GPB.
Binds to 50S subunit at
a unique site,
preventing formation of
the initiation complex
treatment of vancomycin-
resistant E. faecium; & other
infections caused by multiple
drug resistant organism,
MRSA, VRE
Thrombocytopenia,
GI disturbances
Headache
No cross resistance
Streptogramins

Bind to different sites
on 50S subunit,
synergistically inhibiting
protein synthesis
Interferes with distinct step of protein
synthesis
Infections caused by resistant
Gram-positive bacteria (e.g.,
MRSA, VRSA)
Vancomycin-resistant E.
faecium
Hepatotoxicity,
Potent inhibitors of
CYP3A4.

ph 20 DNA synthesis inhibitors

Antibiotic Example PK MOA Resistance Clinical Use Adverse Effects
Sulfonamides Sulfamethoxazole,
Sulfadiazine
Absorbed from
stomach and
small intestine;
peak levels in 2-6
hrs; excreted in
urine
Inhibit folic acid
synthesis by
competing with
PABA
Increased
production of
PABA, decreased
uptake, altered
enzyme affinity
Rarely used alone; combined
with Trimethoprim for UTIs,
respiratory infections,
Pneumocystis jirovecii
pneumonia, toxoplasmosis,
nocardiosis
Hypersensitivity reactions (rashes,
Stevens-Johnson syndrome), GI upset,
crystalluria, hemolytic anemia, especially
in G6PD deficiency
Trimethoprim Trimethoprim Well absorbed
orally,
distributed
widely, including
CSF; excreted in
urine
Inhibits
bacterial
dihydrofolate
reductase
Reduced
permeability,
altered enzyme
affinity
Alone for acute UTIs; combined
with Sulfamethoxazole (TMP-
SMX) for P. jirovecii pneumonia,
respiratory infections,
prostatitis, and various bacterial
infections
Megaloblastic anemia, leukopenia,
granulocytopenia; folinic acid can
ameliorate effects; combined therapy
may cause sulfonamide-associated
adverse effects
Trimethoprim-
Sulfamethoxazole
Co-trimoxazole Oral and IV
forms;
trimethoprim
concentrates in
Combination
inhibits
sequential steps
in folic acid
synthesis,
Combined
resistance
mechanisms of
sulfonamides
Broad spectrum including UTIs,
respiratory infections,
Pneumocystis jirovecii
pneumonia, prostatitis, Shigella,
Combination can cause adverse effects of
both drugs, higher incidence in AIDS
patients: fever, rashes, leukopenia,
diarrhea

6. prostatic and
vaginal fluids
making it
bactericidal
and
trimethoprim
Salmonella, nontuberculous
mycobacteria
Quinolones Ciprofloxacin,
Levofloxacin,
Moxifloxacin
Well absorbed
orally;
bioavailability
80-95%;
metabolized in
liver; excreted by
kidneys
Inhibit bacterial
DNA gyrase and
topoisomerase
IV, preventing
DNA replication
Mutations in
DNA gyrase and
topoisomerase
IV, efflux pumps,
reduced
permeability
Broad spectrum including UTIs,
respiratory infections, GI
infections, bone and joint
infections, some STIs
GI upset, CNS effects (headache,
dizziness), tendonitis and tendon
rupture, QT prolongation,
photosensitivity